Targeted protein degradation taught the field of drug discovery an important lesson: a small molecule doesn’t need to occupy an active site to be therapeutic. It can instead force two proteins into proximity and let the biological consequences of that proximity do the work. Proteolysis-targeting chimeras (PROTACs) proved this principle by recruiting E3 ubiquitin ligases to catalytically destroy disease-driving proteins, and have since matured into a validated clinical modality with degraders such as vepdegestrant reaching regulatory submission [1].

Regulated Induced Proximity Targeting Chimeras — RIPTACs — apply the same induced-proximity logic to a different problem. Rather than degrading a disease target, a RIPTAC uses a tumor-restricted protein as a tether to selectively disable a separate protein that is essential for cell survival, and it does so only inside the cells that express that tether [2]. The concept was formalized by a Yale-associated team working with Halda Therapeutics, and it moved unusually fast from mechanistic proof-of-concept to the clinic: the first RIPTAC, HLD-0915, entered a Phase 1/2 trial in metastatic castration-resistant prostate cancer within roughly two years of the founding publication [3]. Validation continued to compound from there — in November 2025, Johnson & Johnson agreed to acquire Halda Therapeutics for $3.05 billion in cash, described in the trade press as the largest deal yet paid for an induced-proximity platform [4].

That commercial validation has, in turn, exposed the field’s central open problem. Making the linker chemistry that connects two ligands is now a comparatively solved problem; finding two ligands, for a tumor-restricted target protein and an essential effector protein, that actually cooperate to form a functional ternary complex is not. This article walks through how RIPTACs work, how they compare mechanistically to PROTACs, molecular glues, and TCIPs, what the clinical and deal-making record shows so far, and why high-throughput, cell-based screening approaches — including DNA-encoded library (DEL) selection — are increasingly positioned as part of the answer to the field’s pairing bottleneck.

A RIPTAC is a heterobifunctional small molecule: structurally, two ligands joined by a chemical linker, much like a PROTAC. Functionally, though, it is built for a different job. One ligand binds a target protein (TP) — a protein whose expression is restricted to, or strongly enriched in, the diseased cell. In the founding published example, the target protein is the androgen receptor, a well-characterized driver of prostate cancer with expression heavily skewed toward prostate tissue [2]. The second ligand binds an effector protein (EP) — a protein that is essential for cell viability but, critically, is expressed broadly across both healthy and diseased tissue.

On its own, a ligand for a broadly expressed, essential protein would be a poor drug candidate: inhibiting something the cell cannot live without, everywhere it is expressed, is a recipe for toxicity rather than therapy. The RIPTAC’s design solves this by making the two ligands functionally interdependent. The linker is built so that the compound preferentially engages both proteins simultaneously, forcing a stable three-protein (“ternary”) complex between the RIPTAC, the TP, and the EP [2,5]. That complex — and the loss of EP function that follows from it — can only form efficiently in cells that also express the TP. In TP-negative healthy cells, the EP-binding ligand has no tether to anchor a productive complex, and normal EP activity is left largely undisturbed.

Halda’s own publications describe the resulting cellular phenotype as a “hold-and-kill” mechanism: the target protein effectively “holds” the RIPTAC in place long enough for it to disable the effector protein’s function, and that disabled function then drives cell death — selectively, and only in cells expressing the tether [2,3]. A commentary accompanying the founding mechanistic paper in Cell Chemical Biology framed this as “opening the therapeutic window” for essential-protein targets that would otherwise be undruggable on their own [5].

Figure 1. In a target-protein-positive tumor cell, the RIPTAC bridges TP and EP into a ternary complex that disables EP and kills the cell. In a target-protein-negative healthy cell, no productive complex forms, EP function is unaffected, and the cell survives.

RIPTACs sit within a broader and fast-growing family of induced-proximity modalities. Each family member forces two proteins together, but the purpose of that proximity, and the source of the resulting selectivity, differ substantially.

PROTACs recruit an E3 ubiquitin ligase to a disease target, tagging it for destruction via the ubiquitin-proteasome system. Because the ligase acts catalytically, a single PROTAC molecule can support degradation of many target protein copies, and selectivity is driven largely by target expression and “degradability” — how amenable the target’s conformation and cellular trafficking are to productive ternary complex formation with the ligase [1].

Molecular glues are typically monovalent or near-monovalent small molecules that stabilize a novel interface between two proteins that would not otherwise interact — classically an E3 ligase and a neosubstrate, as with the immunomodulatory drugs that redirect cereblon toward new targets. Because molecular glues often lack an obvious bifunctional architecture, their discovery has historically depended more on serendipity than the modular, linker-driven design used for PROTACs and RIPTACs, though systematic chemical-profiling approaches are now closing that gap [6].

TCIPs (transcriptional/chaperone-based inducers of proximity) redirect a disease-associated regulatory machine — for example, a transcription factor or chromatin reader bound to an oncogenic locus — toward an effector that converts that binding event into a therapeutic outcome, such as forced transcription of a pro-apoptotic gene. A 2023 study published in Nature demonstrated this by rewiring bromodomain-containing protein 4 (BRD4) at super-enhancers driving oncogene expression to instead drive expression of the pro-apoptotic gene BCL2L11, killing cancer cells that depend on that oncogenic transcriptional program [7].

RIPTACs, distinct from all three, are explicitly non-degradative. Nothing is destroyed; the essential effector protein is instead sequestered into an inactive ternary complex. Selectivity is not a function of target degradability or of a spontaneously novel interface — it is a function of differential expression of the target protein between diseased and healthy tissue [2]. That reframing matters commercially: it means an essential, otherwise “undruggable” housekeeping protein can become a viable effector, as long as a sufficiently tissue- or tumor-restricted target protein exists to pair it with.

The founding RIPTAC publication, in Cell Chemical Biology, reported selective killing of prostate cancer cells in preclinical models — including models resistant to enzalutamide, a standard-of-care androgen receptor antagonist — while sparing androgen-receptor-negative cells [2]. That result was the proof-of-mechanism the field needed: it showed that a non-degradative, ternary-complex-dependent mechanism could achieve tumor selectivity even against a target (an essential transcriptional/proliferative regulator) that would never be druggable as a standalone inhibitor.

That preclinical work matured into HLD-0915, an oral RIPTAC pairing the androgen receptor with an essential effector protein, which entered a Phase 1/2 clinical trial in metastatic castration-resistant prostate cancer (mCRPC) — the first RIPTAC to reach human testing. A 2025 news feature in Nature Reviews Drug Discovery covering that milestone described the approach as extending induced-proximity pharmacology “beyond protein degraders,” toward tissue-selective target inhibition rather than destruction [3]. A companion perspective in the Journal of Medicinal Chemistry, published the same year, used HLD-0915 as the motivating example for a broader discussion of RIPTAC medicinal chemistry and design principles, underscoring how quickly the modality had moved from a single mechanistic paper to a recognized class worth reviewing in its own right [8].

The clearest signal of validation, though, came from the deal market rather than the clinic. In November 2025, Johnson & Johnson agreed to acquire Halda Therapeutics for $3.05 billion in cash — coverage in Nature Reviews Drug Discovery called it the biggest induced-proximity deal to date, for a company that, at the time, had a single asset in Phase 1/2 [4]. Halda’s president and CEO, Christian Schade, characterized the acquisition as “a tribute to the years of scientific effort to develop this novel, first-in-class modality” [9]. For a platform built on one clinical-stage molecule, that price tag is a strong market signal that large pharmaceutical companies view RIPTACs as a durable new pharmacological category rather than a one-off curiosity.

Halda’s exit accelerated interest across the broader induced-proximity space. In August 2025, Halda and the AI drug-discovery company VantAI announced a computational discovery alliance potentially worth more than $1 billion in payments, explicitly aimed at using structure-prediction and generative modeling to identify new target–effector protein pairs beyond the androgen receptor axis that anchors HLD-0915 [10]. The scale of that alliance is itself informative: a company that has just closed a multi-billion-dollar acquisition is still investing heavily and immediately in better ways to find RIPTAC pairs, which tells you where the field believes the remaining risk sits.

Elsewhere, Flare Therapeutics — a company focused on drugging transcription factors — disclosed that it is advancing an androgen-receptor-directed RIPTAC program through preclinical development, positioned as a companion effort alongside its lead AR(ON) degrader program, backed by an $85 million insider-led Series C financing round closed in mid-2026 [11]. Multiple other oncology-focused biotech and pharma groups are reportedly building early induced-proximity pipelines, with initial efforts still concentrated on nuclear hormone receptors and other transcriptional targets, where tissue-restricted expression patterns are best characterized and easiest to exploit for a target protein.

Once you look across these programs, a pattern emerges: nearly every disclosed RIPTAC candidate still pairs the androgen receptor with an effector protein, and the number of validated, functional target–effector pairs reported publicly remains small relative to the number of plausible candidate combinations that could, in principle, be tried. Linker chemistry connecting two known-good ligands is now a well-trodden medicinal chemistry problem, informed by two decades of PROTAC linker optimization work [1]. Identifying which essential effector protein, paired with which tissue-restricted target protein, will actually cooperate to form a stable, functional ternary complex is not — and unlike ligand potency or linker geometry, that compatibility can’t be fully predicted from structure alone, because it also depends on subcellular localization, relative abundance, and cellular context.

That is precisely the kind of combinatorial search problem that favors empirical, high-throughput approaches over one-pair-at-a-time rational design — and it’s why two very different discovery strategies (VantAI’s computational, structure-based approach and DEL-based empirical screening) are both being pursued as complementary answers to the same underlying constraint. DNA-encoded library selection, in particular, was purpose-built for combinatorial search problems of exactly this shape: screening formats that can interrogate hundreds of millions of candidate binders against a protein in a single experiment, rather than testing designed candidates one at a time, are a natural fit for a field whose main bottleneck is combinatorial pair discovery rather than potency optimization [12].

DNA-encoded libraries work by attaching a unique DNA “barcode” to each member of a combinatorial small-molecule library, so that after an affinity-based selection against a protein target, sequencing the surviving barcodes reveals which chemical structures bound. This lets a single experiment screen library sizes — often hundreds of millions of compounds — that would be entirely impractical with conventional one-compound-at-a-time high-throughput screening, and the approach has matured into a well-established hit-finding technology across the pharmaceutical industry [12].

Critically, this combinatorial capability has already been demonstrated directly against the proximity-inducing molecule problem, not just against conventional single-target binders. A 2024 study in Nature Chemical Biology used a DEL screening strategy to directly discover functional PROTAC-type degraders — bifunctional compounds recruiting the VHL E3 ligase — identifying a potent bromodomain-containing protein 4 (BRD4) degrader, including a novel BRD4-binding ligand, directly from the selection itself, with minimal downstream optimization required [13]. That result is a proof-of-concept for a broader idea: DEL-based selection doesn’t just find binders to a single protein — it can be configured to find and characterize the chemical matter needed for a functional bifunctional molecule, ternary complex formation included.

Applied to RIPTAC discovery specifically, that combinatorial capability addresses two distinct needs simultaneously. First, DEL selection can generate high-quality, novel ligands against each side of a candidate pair independently — screening directly against a tumor-restricted target protein candidate, and separately against an essential effector protein candidate, without requiring either to already have a known, drug-like starting ligand. Second — and this is the piece that matters most for a modality whose selectivity is fundamentally a cellular phenomenon — because RIPTAC selectivity depends on which proteins are actually co-expressed and able to physically form a complex inside a living cell, not merely on binary in vitro affinity, screening formats that operate under physiologically relevant, cellular conditions are especially well matched to this modality’s discovery needs. Assessing differential engagement and complex formation directly in a cellular context, from the earliest stages of hit-finding, means that a candidate pair’s cell-selectivity profile is characterized early, rather than discovered as a costly surprise deep into a medicinal chemistry campaign.

RIPTACs remain a young modality — one validated clinical candidate, one landmark acquisition, and a small but growing set of preclinical follow-on programs. But the underlying design principle — exploit differential expression rather than differential degradability — generalizes well beyond androgen receptor biology in prostate and breast cancer, and the field’s own diagnosis of its limiting factor is unambiguous: target–effector pairing, not linker chemistry, is what is currently constraining how far and how fast the platform concept can expand [4,10]. That diagnosis points directly toward the kind of empirical, cell-based, high-throughput discovery approaches that DNA-encoded library screening platforms were built to deliver. As more validated effector-protein ligands and tissue-restricted target-protein ligands are identified and cataloged across a wider range of cancers and essential cellular machinery, the combinatorial space of viable RIPTAC pairs — and the modality’s reach beyond prostate and breast cancer — should expand accordingly.

1. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov (2022), 21(3), 181-200. DOI: https://doi.org/10.1038/s41573-021-00371-6
2. Raina K, Forbes CD, Stronk R, et al. Regulated induced proximity targeting chimeras—RIPTACs—a heterobifunctional small molecule strategy for cancer selective therapies. Cell Chem Biol (2024), 31(8), 1490-1502. DOI: https://doi.org/10.1016/j.chembiol.2024.07.005
3. Mullard A. Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic. Nat Rev Drug Discov (2025), 24(4), 235-237. DOI: https://doi.org/10.1038/d41573-025-00037-7
4. Mullard A. Halda secures biggest induced-proximity deal yet, with J&J’s US$3 billion buy out. Nat Rev Drug Discov (2025), 25(1), 9. DOI: https://doi.org/10.1038/d41573-025-00190-z
5. Mangano K, Potts PR. Feel the breeze: Opening the therapeutic window with RIPTACs and induced proximity. Cell Chem Biol (2024), 31(8), 1391-1393. DOI: https://doi.org/10.1016/j.chembiol.2024.07.013
6. Mayor-Ruiz C, Bauer S, Brand M, et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat Chem Biol (2020), 16(11), 1199-1207. DOI: https://doi.org/10.1038/s41589-020-0594-x
7. Gourisankar S, Krokhotin A, Ji W, et al. Rewiring cancer drivers to activate apoptosis. Nature (2023), 620(7973), 417-425. DOI: https://doi.org/10.1038/s41586-023-06348-2
8. Ma Z, Zhang C, Shen Q, Zhou J. RIPTACs for Precision Cancer Therapy: A Novel Modality with the Inspiration of HLD-0915 as the First Candidate in Clinical Trials. J Med Chem (2025), 68(11), 10503-10506. DOI: https://doi.org/10.1021/acs.jmedchem.5c01250
9. DDW Staff. Oncology company Halda acquired by Johnson & Johnson. Drug Discovery World (2025). www.ddw-online.com/oncology-company-halda-acquired-by-johnson-johnson-39055-202511
10. BusinessWire. VantAI and Halda Therapeutics Forge Alliance to Discover Next-Generation RIPTAC Medicines. BusinessWire (Aug 19, 2025). www.businesswire.com/news/home/20250819757409/en
11. Flare Therapeutics. Flare Therapeutics Secures $85M in Insider-Led Series C Financing and Appoints Anna Protopapas as Chief Executive Officer. Flare Therapeutics press release (2026). www.flaretx.com/flare-therapeutics-secures-85m-in-insider-led-series-c-financing-and-appoints-anna-protopapas-as-chief-executive-officer
12. Peterson AA, Liu DR. Small-molecule discovery through DNA-encoded libraries. Nat Rev Drug Discov (2023), 22(9), 699-722. DOI: https://doi.org/10.1038/s41573-023-00713-6
13. Mason JW, Chow YT, Hudson L, et al. DNA-encoded library-enabled discovery of proximity-inducing small molecules. Nat Chem Biol (2024), 20(2), 170-179. DOI: https://doi.org/10.1038/s41589-023-01458-4

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Over the past decade, PROTACs (proteolysis-targeting chimeras) and molecular glues have shown that a small molecule doesn’t have to occupy an active site to be a drug — it only has to bring two proteins close enough together, for long enough, for biology to do the rest. By hijacking an E3 ubiquitin ligase and steering it toward a disease-causing protein, these heterobifunctional and monovalent “glue” molecules turned degradation into a programmable, catalytic event, opening up targets that classical inhibitors could never reach [1].

That same induced-proximity logic — recruit an effector enzyme, park it next to a target protein, let mass action and catalysis do the work — is not limited to degradation. It is a general strategy for building tools and drugs around almost any enzyme–substrate relationship, sometimes grouped under the umbrella term “chemical inducers of proximity” (CIPs) [2]. One of the most active frontiers right now is turning that logic on the enzymes that write and erase phosphorylation marks — kinases and phosphatases. Two related but opposite classes of molecules have emerged from this idea, and they increasingly show up in the same sentence in the trade and academic press: PhoRCs (phosphatase-recruiting chimeras) and PhICs (phosphorylation-inducing chimeras), the latter also written PHICS. Together they promise something PROTACs cannot: not the elimination of a protein, but precise, reversible, dial-a-phosphosite control over what it does.

This article explains what PhoRCs and PhICs are, how they work, why pharma is already betting real money on them, and — because Vipergen’s business is finding the small molecules that make modalities like this possible — where DNA-encoded library (DEL) screening fits into discovering them.

PhoRCs (Phosphatase-Recruiting Chimeras) are heterobifunctional molecules built from two binding “warheads” joined by a linker: one arm binds a phosphorylated protein of interest, the other recruits a protein phosphatase. Bringing the two into proximity lets the phosphatase do what it already does naturally — remove a phosphate group — but now directed at a specific site on a specific protein, instead of acting broadly across the phosphatase’s normal substrate pool.

PhICs (Phosphorylation-Inducing Chimeras, or Phosphorylation-Inducing Chimeric small molecules — PHICS) work the same way in reverse: one arm binds the target protein, the other recruits a kinase, and the induced proximity drives the kinase to phosphorylate the target, including at sites — or on substrates — the kinase would never naturally reach on its own. The concept was introduced by Siriwardena, Choudhary and colleagues in 2020, who coined the term “PhICs” and showed that a synthetic small molecule could redirect kinases such as AMPK and PKC to phosphorylate BRD4 and other proteins, with the induced phosphorylation showing dose-dependence, a hook effect at high concentration, and sensitivity to linker length — all hallmarks of a genuine ternary-complex mechanism rather than simple off-target kinase activation [3].

A closely related and slightly earlier term, PhosTAC (phosphorylation-targeting chimera), was introduced independently by the Crews lab at Yale in 2021 to describe bifunctional molecules that recruit a phosphatase to dephosphorylate a target protein — functionally the same concept as a PhoRC, and the two terms are now used almost interchangeably [4]. A 2023 review usefully groups PhoRCs, PhICs and PhosTACs together under a broader “TACnology” umbrella of heterobifunctional post-translational-modification (PTM) inducers, alongside PROTACs, LYTACs and related proximity-based modalities [5]. That framing is a good way to think about where PhoRCs and PhICs fit: PROTACs and molecular glues answer “how do I get rid of this protein”; PhoRCs and PhICs answer “how do I change what this protein is doing, without changing how much of it there is.”

The mechanics are what make this modality genuinely interesting to drug hunters, not just a structural-biology curiosity. Because a PhoRC or PhIC doesn’t need to occupy an active site or block a protein–protein interaction to have an effect — the phosphatase or kinase it recruits does the actual chemistry — a single small-molecule chimera can act catalytically: one molecule can drive dephosphorylation or phosphorylation across many copies of the target protein, provided the ternary complex forms and dissociates productively [6]. That is a fundamentally different pharmacology from a classical inhibitor, which is typically stoichiometric and occupies its target for as long as it stays bound.

This gives the modality a distinctive experimental signature. Activity depends on linker length and rigidity — too short or too long, and the ternary complex can’t assemble productively. A hook effect appears at high compound concentration, because excess chimera saturates both binding sites separately instead of bridging them together. And because the “catalyst” being recruited is a specific kinase or phosphatase isoform rather than an entire enzyme family, PhoRCs and PhICs can achieve a level of isoform selectivity that small-molecule kinase or phosphatase inhibitors — which usually bind a conserved ATP pocket shared across dozens of related enzymes — struggle to match [3].

The current generation of PhoRC and PhosTAC molecules leans heavily on natural phosphatase-recognition motifs to build the phosphatase-recruiting arm. For protein phosphatase 1 (PP1), that is often a short peptide built around the “RVxF” docking motif that PP1’s natural regulatory subunits use; for PP5, chimeras have instead used ligands directed at its regulatory TPR domain [5]. That choice is a double-edged sword. On one hand, it borrows validated, high-affinity recognition biology straight from nature. On the other, short linear peptide motifs are exactly the kind of chemical matter medicinal chemists try to avoid in an oral drug: they tend to violate Lipinski’s Rule of Five, are typically membrane-impermeant, and are degraded quickly in circulation — which has kept most published PhoRCs and PhosTACs as cell-biology tools rather than clinical candidates so far [5]. PhICs face a related but distinct challenge on the other side of the molecule: kinase-recruiting warheads are usually derived from ATP-competitive kinase inhibitors, which is good for binding potency but can also block the recruited kinase’s own catalytic activity toward its natural substrates — a design trade-off that has to be engineered around case by case, for example by using a partial or allosteric kinase binder rather than a fully occupying inhibitor [3].

It helps to place PhoRCs and PhICs next to the induced-proximity modalities most drug discovery teams already know well.

The practical upshot: PROTACs and molecular glues are best suited to proteins you want gone entirely — oncogenic drivers, scaffolding proteins with no tractable active-site pocket, transcription factors. PhoRCs and PhICs are best suited to proteins you don’t want to remove, only to switch — receptors, adaptor proteins, or enzymes whose disease-relevant behavior, localization, or stability is controlled by a single phosphorylation event that can now be dialed up or down externally, in either direction, reversibly [2].

Phosphorylation is one of biology’s most common and most reversible control switches — it governs enzyme activation, protein–protein interactions, subcellular trafficking, and stability, often through a single phosphosite. That makes it an attractive lever for two kinds of target that resist both classical inhibitors and degraders: proteins whose disease-relevant behavior is a specific phosphorylation state rather than the protein’s mere presence, and proteins where tunable, reversible, temporally controlled modulation is preferable to a one-way switch.

Cancer signaling is one clear example. Zhang and colleagues built a PP5-recruiting chimera against ASK1 (apoptosis signal-regulating kinase 1), accelerating its dephosphorylation and inactivation and demonstrating antiproliferative activity in cancer cell models — using a phosphatase-recruiting chimera to shut down a kinase’s activating phosphorylation, rather than blocking the kinase’s ATP pocket directly [7].

Alzheimer’s disease and other tauopathies are another. Hyperphosphorylated tau aggregates into neurofibrillary tangles, and the Crews lab showed that a PhosTAC recruiting protein phosphatase 1 could selectively drive dephosphorylation of tau at disease-associated sites in neurons, reducing the pathogenic, aggregation-prone form without changing total tau levels [8]. A 2025 follow-up study used PP5-recruiting chimeras to achieve a related effect through a different phosphatase, reinforcing that more than one phosphatase can be redirected against the same pathogenic phosphosite depending on which is most tractable to recruit chemically [9].

Drug resistance is a third, particularly commercially relevant angle. Acquired resistance to EGFR tyrosine kinase inhibitors is a major clinical problem in non-small-cell lung cancer, and a 2025 study in Nature Communications engineered an aptamer-directed phosphatase-recruiting chimera that dephosphorylates EGFR directly, resensitizing resistant cells to gefitinib and shrinking tumors substantially further than the kinase inhibitor alone in xenograft models [10]. Because the mechanism dephosphorylates the receptor rather than degrading or inhibiting it, it sidesteps resistance mutations that act specifically on the ATP-binding pocket — a resistance-evasion strategy that neither classical kinase inhibitors nor degraders can offer in the same way.

This is not purely an academic curiosity. In September 2022, Photys Therapeutics launched with $75 million in Series A financing led by MPM Capital, with participation from corporate investors including Merck and Eli Lilly, specifically to build a pipeline around PHICS — its trademarked term for phosphorylation-inducing chimeric small molecules [11]. The company was co-founded by Dr. Amit Choudhary of Brigham and Women’s Hospital and the Broad Institute of MIT and Harvard, together with Longwood Fund — the same Choudhary lab that published the original PhICs concept in 2020 [3], giving the company a direct line from the founding academic paper to a funded, pharma-partnered pipeline within two years [11].

The clearest sign that big pharma sees this as more than a platform bet came in December 2024, when Novo Nordisk signed a collaboration with Photys worth up to $186 million in upfront, development and commercial milestone payments plus tiered royalties, to apply PHICS technology to an undisclosed cardiometabolic target — part of Novo’s broader push beyond GLP-1 medicines into areas such as MASH and chronic kidney disease. Under the deal, Photys runs discovery and preclinical work while Novo advances the resulting molecules through IND-enabling studies and into the clinic [12]. Photys has continued to build a broader induced-proximity pipeline alongside its PHICS platform, including a PROTAC-based IRAK4 degrader that entered Phase 1 clinical trials in 2026 — evidence that the company, and the field more broadly, are treating phosphorylation-targeting chimeras as one tool in a wider induced-proximity toolbox rather than a one-off idea [12].

For a modality that didn’t have a settled name in the literature until 2020–2021, that is a fast trajectory from first paper to nine-figure pharma partnership, and it means the pressure to find better, more drug-like PhoRC and PhIC ligands, faster, is now a commercial priority, not only an academic one.

The design challenges described above translate directly into a discovery problem. Most published PhoRCs and PhosTACs use peptide-derived phosphatase-recruiting motifs, because those are the ligands biology already validated — but peptides are hard to turn into oral drugs, and there is no equivalent, exhaustively mapped shelf of small-molecule phosphatase or kinase “presenter” ligands to draw on the way PROTAC chemists can now draw on a well-characterized set of CRBN and VHL binders [5]. What the field needs is what PROTAC discovery needed a decade ago: a fast, unbiased way to find small-molecule, drug-like binders for the recruiting arm, and — just as importantly — a way to test which combinations of target-binder, linker, and recruiter-binder actually assemble into a productive ternary complex, rather than two independent binary interactions that simply happen not to interfere with each other.

That is a screening problem as much as a synthesis problem, and it is one DNA-encoded library technology has already started to solve for the closely related case of PROTACs.

DNA-encoded libraries let you screen millions to billions of drug-like small molecules in a single tube, with each compound’s structure recorded in a DNA barcode that is read out by sequencing after selection — exactly the throughput needed to find rare, non-peptidic binders for a new target class. DEL screening has already been adapted specifically for induced-proximity discovery, not just simple binary binding. Mason and colleagues at the Broad Institute built a “CIP-DEL” library of roughly a million DNA-encoded, VHL-directed bifunctional compounds and screened it directly against BRD4 in the presence versus absence of the VHL–elongin complex, using differential enrichment to identify compounds that specifically formed a productive ternary complex — not just molecules that bound BRD4 alone — pulling out a degrader with single-digit-nanomolar potency straight from the selection [13]. A separate DEL-based approach used similar logic to optimize an existing PROTAC’s ternary-complex geometry, screening a DNA-encoded set of linker and warhead variants against the target in the presence of the E3 ligase to enrich for the combinations that assembled most efficiently [14].

That logic maps directly onto PhoRCs and PhICs: instead of screening a DEL against a target protein alone, or against a target plus an E3 ligase, you screen it against a target protein in the presence of a specific phosphatase or kinase “presenter,” and let differential enrichment surface the small molecules that preferentially assemble a productive three-way complex. DEL screening has also already been shown to find drug-like binders directed specifically at kinases — including, in an early landmark study, a covalent kinase inhibitor discovered by cross-screening a DNA-encoded small-molecule library against a DNA-encoded protein library — demonstrating that DEL formats can resolve the kind of selective, non-ATP-pocket kinase engagement that a PhIC’s recruiting arm would ideally use [15].

This is where Vipergen’s screening platforms are particularly well suited to the problem. Vipergen’s cellular Binder Trap Enrichment (cBTE) technology screens DNA-encoded libraries directly inside living cells, under native physiological conditions, rather than against a purified protein reconstituted in a test tube. For a modality whose entire mechanism of action depends on a kinase or phosphatase that is present, correctly folded, and doing its normal biology inside the cell, screening in that same physiological context is a meaningfully better proxy for whether a candidate PhoRC or PhIC will actually work once delivered into a real cell — compared with screening against a purified enzyme domain in isolation, which can miss the effects of native regulatory subunits, scaffolding proteins, or subcellular localization. Vipergen’s solution-based Binder Trap Enrichment (BTE) platform offers a complementary in-vitro route where a purified, well-behaved phosphatase or kinase construct is available and a defined biochemical readout is preferred. And because Vipergen’s YoctoReactor library synthesis ensures a tight match between each compound’s DNA barcode and its actual chemical structure, hits from a demanding, low-signal ternary-complex screen can be trusted with confidence — which matters more, not less, for a target class where the readout depends on three molecules coming together correctly rather than two.

Because every hit that comes out of a Vipergen DEL screen is barcode-traceable back to its exact structure, both halves of a future bifunctional molecule — the target-binding warhead and the enzyme-recruiting warhead — can in principle be discovered from DEL panels run against the target and against the desired kinase or phosphatase respectively, and then combined synthetically off-DNA. That is the same two-warhead discovery workflow the field already uses for PROTACs and molecular glues, simply pointed at a different effector protein.

PROTACs took roughly two decades to go from a single early proof-of-concept to approved and late-stage clinical candidates, and their progress accelerated enormously once the field had fast, unbiased ways to find drug-like E3-ligase and target warheads. PhoRCs and PhICs are earlier on that same curve — young enough that most published examples are still peptide-based cell-biology tools, but validated enough, and now funded well enough by programs like the Novo Nordisk–Photys collaboration, that the race to find better, smaller, more drug-like ligands for both halves of the molecule is genuinely underway.

That is exactly the kind of hit-finding problem DNA-encoded library screening was built to solve, and it is where Vipergen’s in-cell and in-vitro DEL platforms come in — whether the target is a classic degradation candidate, a molecular-glue opportunity, or the next phosphatase- or kinase-recruiting chimera. If you are working on a target where changing a protein’s phosphorylation state, rather than removing the protein altogether, is the better therapeutic strategy, get in touch to discuss how DEL screening can find the binders you need.

[1] Tsai JM, Nowak RP, Ebert BL, Fischer ES. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol (2024), 25(9), 740-757. https://doi.org/10.1038/s41580-024-00729-9

[2] Liu X, Ciulli A. Proximity-based modalities for biology and medicine. ACS Cent Sci (2023), 9(7), 1269-1284. https://doi.org/10.1021/acscentsci.3c00395

[3] Siriwardena SU, Munkanatta Godage DNP, Shoba VM, Lai S, Shi M, Wu P, et al. Phosphorylation-inducing chimeric small molecules. J Am Chem Soc (2020), 142(33), 14052-14057. https://doi.org/10.1021/jacs.0c05537

[4] Chen PH, Hu Z, An E, Okeke I, Zheng S, Luo X, et al. Modulation of phosphoprotein activity by phosphorylation targeting chimeras (PhosTACs). ACS Chem Biol (2021), 16(12), 2808-2815. https://doi.org/10.1021/acschembio.1c00693

[5] Heitel P. Emerging TACnology: heterobifunctional small molecule inducers of targeted posttranslational protein modifications. Molecules (2023), 28(2), 690. https://doi.org/10.3390/molecules28020690

[6] Sun Y, Zhou R, Hu J, Feng S, Hu Q. Reversible control of kinase signaling through chemical-induced dephosphorylation. Commun Biol (2024), 7, 1073. https://doi.org/10.1038/s42003-024-06771-9

[7] Zhang Q, Wu X, Zhang H, Wu Q, Fu M, Hua L, et al. Protein phosphatase 5-recruiting chimeras for accelerating apoptosis-signal-regulated kinase 1 dephosphorylation with antiproliferative activity. J Am Chem Soc (2023), 145(2), 1118-1128. https://doi.org/10.1021/jacs.2c10759

[8] Hu Z, Chen PH, Li W, Douglas T, Hines J, Liu Y, et al. Targeted dephosphorylation of tau by phosphorylation targeting chimeras (PhosTACs) as a therapeutic modality. J Am Chem Soc (2023), 145(7), 4045-4055. https://doi.org/10.1021/jacs.2c11706

[9] Gu J, He C, Han Z, Huang Q, He Y, Lu Y, et al. Protein phosphatase 5-recruiting chimeras for accelerating tau dephosphorylation. ACS Chem Biol (2025), 20(6), 1347-1360. https://doi.org/10.1021/acschembio.5c00165

[10] Zhou Z, Liu Y, Wang Y, Jiang H, Chen T, Zhu Y, et al. Engineering aptamer-directed phosphatase recruiting chimeras: a strategy for modulating receptor function and overcoming drug resistance. Nat Commun (2025), 16, 3919. https://doi.org/10.1038/s41467-025-59098-2

[11] Business Wire. Photys Therapeutics debuts with $75 million Series A funding to advance new class of bifunctional molecules for precision phosphorylation to modulate and repair disease-driving proteins (2022, September 8). https://www.businesswire.com/news/home/20220908005074/en/Photys-Therapeutics-Debuts-with-75-Million-Series-A-Funding-to-Advance-New-Class-of-Bifunctional-Molecules-for-Precision-Phosphorylation-to-Modulate-and-Repair-Disease-Driving-Proteins

[12] Fierce Biotech. Novo Nordisk taps Photys for $186M cardiometabolic collab. (2024, December 18). https://www.fiercebiotech.com/biotech/novo-nordisk-taps-photys-186m-deal-aim-proximity-based-therapeutics-platform

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A DUBTAC links a target-protein ligand to a deubiquitinase-recruiting ligand. The resulting ternary complex lets the deubiquitinase strip ubiquitin marks from the target, so it escapes the proteasome and accumulates instead of being degraded [1].

For nearly two decades, targeted protein degradation has dominated the conversation around proximity-inducing therapeutics. PROTACs and molecular glues taught the field how to hijack the cell’s ubiquitin-proteasome system to eliminate disease-driving proteins, and that success created an obvious question: could the same bifunctional logic run in reverse? Deubiquitinase-targeting chimeras, or DUBTACs, answer yes. Instead of tagging a protein for destruction, a DUBTAC recruits a deubiquitinating enzyme to strip away the ubiquitin marks that would otherwise send a protein to the proteasome — rescuing it from degradation instead of causing it [1]. That single mechanistic inversion opens an entire therapeutic territory that classical degraders cannot reach: diseases caused by too little of a protein, not too much.

This article explains what a DUBTAC is, how it works at the molecular level, how it compares with PROTACs and molecular glues, which targets have already been validated in the peer-reviewed literature, where the field’s real bottlenecks sit, and how DNA-encoded library (DEL) screening is positioned to accelerate discovery of the next generation of DUB-recruiting ligands.

A DUBTAC is a heterobifunctional small molecule: two ligands joined by a chemical linker, where one end binds a disease-relevant target protein and the other end binds a deubiquitinating enzyme (a “DUB”). Bringing the two together in a ternary complex lets the DUB act on the target, removing ubiquitin chains that would otherwise mark it for destruction. The name deliberately echoes PROTAC (PROteolysis TArgeting Chimera), the founding bifunctional degrader modality first described by Sakamoto and colleagues in 2001, which uses the identical bivalent design principle to recruit an E3 ubiquitin ligase instead [2].

To understand why that swap matters, it helps to recall how the ubiquitin-proteasome system (UPS) normally works. E3 ubiquitin ligases attach chains of ubiquitin — most consequentially chains linked through lysine 48 (K48) — onto substrate proteins. The 26S proteasome recognizes K48-linked polyubiquitin as a degradation signal and destroys the tagged protein. Deubiquitinating enzymes, of which the human genome encodes around 100, run this process in reverse: they hydrolyze the isopeptide bonds holding ubiquitin chains together, editing or erasing the degradation signal entirely. This bidirectional ubiquitin cycle is one of the cell’s primary mechanisms for controlling protein abundance, and it was characterized in foundational work by Hershko and Ciechanover, for which they later shared the Nobel Prize in Chemistry [3]. A DUBTAC is, in effect, a synthetic switch that lets a chemist redirect a chosen DUB’s natural editing activity onto a chosen target protein.

The mechanism follows a clear sequence:

1. Target engagement. One arm of the DUBTAC binds a surface pocket on the disease-relevant target protein — the same kind of ligand-discovery problem faced in any small-molecule drug discovery campaign.
2. DUB recruitment. The other arm binds a deubiquitinase, typically at a ligandable cysteine or an allosteric pocket rather than the catalytic active site itself, since occupying the active site would block the enzyme’s function.
3. Ternary complex formation. Because both ligands are tethered by a linker, the DUBTAC brings the target protein and the DUB into physical proximity, forming a three-way (ternary) complex analogous to the target–PROTAC–E3-ligase complex in degrader pharmacology.
4. Deubiquitination. With the DUB’s catalytic domain now positioned next to the target’s ubiquitin chains, the enzyme hydrolyzes the K48-linked chains and removes the degradation signal.
5. Stabilization. Stripped of its “destroy me” tag, the target protein escapes proteasomal recognition, its half-life increases, and it accumulates to higher steady-state levels than in the untreated cell.

The founding demonstration of this mechanism came from Nomura and colleagues at UC Berkeley and Novartis, who screened a covalent-fragment library against the K48-specific deubiquitinase OTUB1 and identified EN523, a ligand that binds a non-catalytic allosteric cysteine (C23) on OTUB1 without inhibiting its enzymatic activity. Linking EN523 to lumacaftor — an existing, clinically used corrector of the misfolded cystic fibrosis transmembrane conductance regulator (CFTR) — produced the first DUBTAC, which stabilized ΔF508-CFTR protein levels and restored chloride channel function in patient-derived cells more effectively than lumacaftor alone. The same study showed the approach generalizes: an OTUB1-recruiting DUBTAC also stabilized the tumor-suppressor kinase WEE1 in hepatoma cells, establishing that a single DUB recruiter can be paired with different target ligands to stabilize structurally unrelated proteins [1].

DUBTACs belong to a broader family of induced-proximity, or “chemically induced proximity,” modalities that also includes PROTACs and molecular glues. All three exploit the same basic insight — that forcing two proteins into unnatural proximity can redirect one protein’s enzymatic activity onto the other — but they differ in design and in the pharmacological outcome they produce [4].

PROTACs and DUBTACs share a bivalent architecture — a target ligand and an effector ligand joined by a linker — so many of the same medicinal chemistry principles (linker length and geometry, ternary complex cooperativity, cell permeability, degrader/stabilizer “hook effect”) carry over between the two modalities [4][6]. Molecular glues are mechanistically distinct: a single, typically smaller molecule stabilizes or creates a protein–protein interface directly, without the explicit two-ligand-plus-linker design of a bifunctional chimera [5]. Where DUBTACs are unambiguous in outcome — they stabilize — some molecular glues can also drive degradation (as with the glues that recruit substrates to cereblon), so modality and outcome should not be assumed to map one-to-one.

The first two decades of targeted protein degradation were, almost by necessity, focused on diseases driven by a gain-of-function or overexpressed protein — an oncogenic kinase, a hormone receptor, a transcription factor active in the wrong context. PROTACs and molecular glues are extraordinarily well suited to that problem: remove the offending protein and the disease-driving signal disappears.

But a large share of human disease runs in the opposite direction. Loss-of-function mutations, accelerated turnover of an otherwise-functional protein, and premature degradation of tumor-suppressive proteins all cause disease through a deficit, not an excess, of protein activity. Classical small-molecule pharmacology struggles here, because there is often no enzymatic pocket to inhibit — the therapeutic goal is to have more of the protein around, correctly folded and functioning, not less. DUBTACs give medicinal chemists a direct chemical route to that goal: instead of searching for an activator of a protein’s existing function, they can intercept the degradation machinery upstream and let the stabilized protein do the rest [6]. As reviewed by Ma and colleagues, this reframes an entire category of previously intractable “undruggable” loss-of-function biology as addressable with the same bifunctional-molecule toolkit that made targeted degradation successful [6].

Although the modality is only a few years old, a growing set of peer-reviewed studies has validated DUBTACs across genuinely different target classes and disease areas.

Cystic fibrosis — CFTR. The founding 2022 study remains the field’s clearest proof of concept: an OTUB1-recruiting DUBTAC built on the clinical CFTR corrector lumacaftor stabilized ΔF508-CFTR and restored chloride channel conductance in patient-derived cells, outperforming lumacaftor alone [1]. Because CFTR-directed correctors and potentiators are already an approved drug class, this example illustrates a direct, near-term path from an existing therapeutic ligand to a next-generation DUBTAC.

Innate immunity — cGAS. In 2025, Deng and colleagues reported the first-in-class DUBTAC directed at cyclic GMP-AMP synthase (cGAS), the cytosolic DNA sensor that initiates type-I interferon signaling. Their molecule stabilized and activated cGAS, demonstrating that DUBTACs can be used not only to rescue disease-associated loss-of-function variants but also to pharmacologically amplify a signaling protein’s normal activity by protecting it from turnover [7].

Metabolic signaling — AMPK. Liu and colleagues built a USP7-recruiting DUBTAC to stabilize AMP-activated protein kinase (AMPK), a central regulator of cellular energy metabolism, showing that the modality extends beyond OTUB1 to other well-characterized, ligandable deubiquitinases [8].

Oncology — tumor suppressors via USP28. Wang and colleagues designed USP28-based DUBTACs to stabilize tumor-suppressive substrates as an anticancer strategy, extending the modality’s DUB toolbox further and reinforcing that multiple, chemically distinct DUBs can each anchor a viable DUBTAC platform [9].

Oncology — tumor-suppressive E3 ligases. In a mechanistically elegant twist, Chen and colleagues used DUBTACs to stabilize E3 ligase proteins that are themselves tumor suppressors, showing that the modality can rescue components of the ubiquitin system itself when their loss — rather than a downstream substrate’s loss — is what drives disease [10].

Broadening the DUB toolbox — USP1. Most recently, Qian and colleagues demonstrated that USP1 can be harnessed as a DUBTAC effector for targeted protein stabilization, adding a fourth validated deubiquitinase (alongside OTUB1, USP7, and USP28) to the field’s expanding recruiter toolkit [11].

Taken together, these studies span cystic fibrosis, innate immunity, metabolic disease, and oncology, and they validate at least four structurally distinct DUBs as viable recruitment handles — evidence that the mechanism is general rather than a one-off curiosity tied to a single enzyme or target.

DUBTACs inherit the standard medicinal chemistry liabilities of any bifunctional molecule — molecular weight, cell permeability, and oral bioavailability all need active management, just as they do for PROTACs [4][6]. Two challenges are more specific to this modality:

DUB ligand scarcity. E3 ligase pharmacology benefited enormously from a small number of highly ligandable, well-characterized ligases (cereblon, VHL) that anchored the first wave of PROTACs. The human deubiquitinase family is considerably larger — on the order of 100 enzymes across several structural subfamilies — but far fewer of them have a validated, selective small-molecule binder. Each new DUB recruiter (OTUB1, USP7, USP28, USP1, and others) currently represents a genuine discovery campaign in its own right rather than a reusable, off-the-shelf handle [6][11].

Selectivity and catalytic-site avoidance. Because occupying a DUB’s catalytic site would simply inhibit the enzyme rather than redirect it, useful DUB recruiters generally need to bind an allosteric or non-catalytic site — as EN523 does at OTUB1’s cysteine 23 — while still enabling productive positioning of the ternary complex. Finding such sites, and confirming they don’t cause off-target deubiquitination of unrelated substrates, adds a layer of complexity beyond standard ligand discovery [1][6].

As of 2026, DUBTACs remain a preclinical, tool-compound-stage modality: no DUBTAC has yet advanced into human clinical trials. What has grown rapidly is the depth of peer-reviewed mechanistic validation — from a single 2022 proof of concept to independent, multi-target confirmation across at least four DUBs and four therapeutic areas within about three years [1][7][8][9][10][11]. That trajectory mirrors the early years of PROTAC development, where a comparable run of academic validation preceded the modality’s move into industry pipelines and, eventually, the clinic [4]. The current bottleneck is not proof of mechanism — it is the pace at which new, selective DUB-recruiting chemical matter can be discovered [6].

That bottleneck is precisely the kind of problem DNA-encoded library (DEL) screening was built to solve. A DEL couples each small molecule in a combinatorial library to a unique DNA barcode, allowing libraries of hundreds of millions to billions of compounds to be pooled, affinity-selected against a target in a single experiment, and deconvoluted by sequencing rather than one-compound-at-a-time testing [12]. That scale is a direct answer to the DUB ligand scarcity problem described above: rather than starting from a small, hand-curated fragment set and hoping to find an allosteric binder, a DEL campaign can sample chemical space broadly enough to find rare, non-obvious pockets on a chosen deubiquitinase — exactly the kind of site EN523 occupies on OTUB1.

DEL screening is useful on both arms of a DUBTAC. Against the DUB itself, a selection can be designed to enrich for ligands at a specific allosteric or non-catalytic surface rather than the active site, and to counter-screen against related DUB family members for selectivity up front. Against the target protein, the same technology that has already been applied to PROTAC and molecular glue discovery for degrader development applies unchanged, since the target-binding ligand-discovery problem is identical in either modality.

Vipergen’s DEL platform is built specifically for this kind of target-first screening. YoctoReactor® synthesizes DEL libraries of hundreds of millions of drug-like small molecules with a purification step after each synthesis round, ensuring a reliable match between a library member’s chemical structure and its DNA barcode — a property that matters enormously when the hit rate against a difficult allosteric pocket is expected to be low. Binder Trap Enrichment® (BTE) performs solution-based selection against a purified protein target with a low false-positive rate, well suited to screening directly against a recombinant DUB domain. Cellular Binder Trap Enrichment® (cBTE) goes a step further, enabling selection directly in living cells without requiring a purified target protein at all — relevant for a deubiquitinase whose relevant conformation or post-translational state may be difficult to reconstitute outside a cellular context [13].

For a discovery program pursuing a next-generation DUBTAC — whether against one of the four validated DUBs or a novel one — this combination of massive library scale, code-compound fidelity, and both in-solution and in-cell selection formats addresses the central rate-limiting step the DUBTAC field currently faces: finding selective, allosteric, non-inhibitory ligands for deubiquitinating enzymes.

For the broader landscape of next-generation induced-proximity modalities beyond PROTACs — including RIPTACs, PHOTACs, and other emerging chimeras alongside DUBTACs — see Next-Generation Targeted Protein Degradation: Beyond Classical PROTACs. For the classical degrader side of the same design logic, see PROTACs and E3 Ligases: Expanding the Toolbox for Targeted Protein Degradation and How Molecular Glue is Transforming Drug Discovery.

Vipergen applies its YoctoReactor, BTE, and cBTE technologies to proximity-inducing molecule discovery across the full spectrum of induced-proximity modalities — PROTACs, molecular glues, and emerging chimeras such as DUBTACs — as well as to traditionally difficult target classes including protein–protein interactions, transcription factors, and membrane proteins. For a DUBTAC or other stabilization-focused program, that means the ability to screen directly against a deubiquitinase target, in solution or in a cellular context, at a library scale designed to find the rare allosteric binders this modality depends on.

If you are exploring a targeted protein stabilization or DUBTAC discovery program, get in touch with Vipergen’s team to discuss how DEL screening can be applied to your target.

DUBTACs invert the logic that made PROTACs successful: rather than recruiting an E3 ligase to destroy a target, they recruit a deubiquitinase to protect one. That single change opens a therapeutic space — loss-of-function and premature-degradation disease biology — that classical degraders cannot address. Peer-reviewed validation has moved quickly, from a single 2022 proof of concept in cystic fibrosis to independently confirmed stabilization of targets across oncology, innate immunity, and metabolic disease, using at least four chemically distinct deubiquitinases as recruitment handles. The modality’s central bottleneck today is chemical matter: selective, allosteric, non-inhibitory ligands for deubiquitinating enzymes remain scarce relative to the well-trodden E3 ligase toolkit. DNA-encoded library screening — searching hundreds of millions of compounds against a DUB target in solution or directly in cells — is built for exactly that discovery problem, and is well positioned to help move DUBTACs from academic proof of concept toward drug candidates.

[1] Henning NJ, Boike L, Spradlin JN, et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol (2022), 18(4), 412-421. https://doi.org/10.1038/s41589-022-00971-2

[2] Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A (2001), 98(15), 8554-8559. https://doi.org/10.1073/pnas.141230798

[3] Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem (1998), 67(1), 425-479. https://doi.org/10.1146/annurev.biochem.67.1.425

[4] Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov (2022), 21(3), 181-200. https://doi.org/10.1038/s41573-021-00371-6

[5] Schreiber SL. The rise of molecular glues. Cell (2021), 184(1), 3-9. https://doi.org/10.1016/j.cell.2020.12.020

[6] Ma Z, Zhou M, Chen H, Shen Q, Zhou J. Deubiquitinase-targeting chimeras (DUBTACs) as a potential paradigm-shifting drug discovery approach. J Med Chem (2025), 68(7), 6897-6915. https://doi.org/10.1021/acs.jmedchem.4c02975

[7] Deng Z, Chen L, Qian C, et al. The first-in-class deubiquitinase-targeting chimera stabilizes and activates cGAS. Angew Chem Int Ed (2025), 64(3), e202415168. https://doi.org/10.1002/anie.202415168

[8] Liu J, Hu X, Luo K, et al. USP7-based deubiquitinase-targeting chimeras stabilize AMPK. J Am Chem Soc (2024), 146(16), 11507-11514. https://doi.org/10.1021/jacs.4c02373

[9] Wang Z, Qian C, Xiong Y, et al. USP28-based deubiquitinase-targeting chimeras for cancer treatment. J Am Chem Soc (2025), 147(16), 13754-13763. https://doi.org/10.1021/jacs.5c01889

[10] Chen L, Deng Z, Xiong Y, et al. Deubiquitinase-targeting chimeras mediated stabilization of tumor suppressive E3 ligase proteins as a strategy for cancer therapy. J Am Chem Soc (2025), 147(33), 29875-29883. https://doi.org/10.1021/jacs.5c06306

[11] Qian C, Wang Z, Xiong Y, et al. Harnessing the deubiquitinase USP1 for targeted protein stabilization. J Am Chem Soc (2025), 147(17), 14564-14573. https://doi.org/10.1021/jacs.5c01662

[12] Goodnow RA Jr, Dumelin CE, Keefe AD. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat Rev Drug Discov (2017), 16(2), 131-147. https://doi.org/10.1038/nrd.2016.213

[13] Vipergen. We present 3 technologies for DNA encoded libraries (DEL). Vipergen A/S. Accessed September 2026. https://www.vipergen.com/technology/

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For most of the history of small-molecule drug discovery, the first question about any new target was whether it had a pocket worth blocking. Targeted protein degradation asks something else: can the protein be marked for disposal instead? The distinction matters, because a large share of the proteins that drive disease have no active site an inhibitor could usefully occupy.

A PROTAC (PROteolysis-TArgeting Chimera) is a bifunctional small molecule that removes a protein rather than blocking it. One end binds the protein of interest, the other binds an E3 ubiquitin ligase, and a chemical linker holds the two ends together. Once the target and the ligase are held close enough together, the cell’s own quality-control machinery does the rest and tags the target for disposal.
The concept was demonstrated in 2001, when a chimeric molecule was used to recruit a target protein to an SCF (Skp1–Cullin–F-box) ubiquitin ligase complex, resulting in ubiquitination and degradation [1].

Classical inhibitors work by occupancy. A drug molecule sits in a binding pocket, and for as long as it stays there the protein cannot do its job. The effect lasts only while the drug is bound, and getting it to bind tightly usually requires a deep, well-defined pocket.

PROTACs work differently. A single PROTAC molecule can bring one copy of the target to the ligase, trigger its ubiquitination, and then be released to repeat the cycle with another copy. Because the molecule is recycled rather than consumed, relatively low drug concentrations can drive substantial degradation, and the effect persists until the cell resynthesises the protein [2].

Two practical consequences follow. Degradation removes every function of a protein at once, including scaffolding and protein–protein interaction roles that an active-site inhibitor would leave intact. And because the protein is gone rather than blocked, degraders can overcome some resistance mutations that blunt occupancy-based drugs [2].

Table 1. Degraders versus traditional small-molecule inhibitors at a glance

Every PROTAC depends on an E3 ubiquitin ligase. E3 ligases are the substrate-recognition components of the ubiquitin–proteasome system, which is the cell’s main route for regulated protein turnover. Their normal job is to select specific proteins and transfer ubiquitin tags onto them.

A PROTAC reprograms that selectivity by presenting the ligase with a new, non-natural substrate. Without a ligand that engages an E3 ligase there is no PROTAC, and as this article will show, the availability of E3-ligase-binding chemistry has become the single biggest factor shaping what targeted protein degradation can and cannot do [6].

The ubiquitin–proteasome system is the cell’s regulated waste-disposal pathway. Proteins destined for destruction are first marked with chains of ubiquitin, a small protein tag. The tagging runs through a three-enzyme cascade: an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase that supplies substrate specificity. Once a protein carries a sufficient polyubiquitin chain, the 26S proteasome recognises it, unfolds it, and breaks it down into peptides.

A PROTAC hijacks the final, specificity-determining step. By tethering its target to an E3 ligase, it ensures the target receives the ubiquitin marks that send it to the proteasome [1][2].

Every PROTAC is built from three parts, and each is a design lever.

• The target warhead is the ligand that binds the protein of interest. It does not need to inhibit the target; it only needs to bind it. This is why proteins long written off as undruggable can become tractable. A shallow or functionally irrelevant binding site that would be useless for an inhibitor can still serve as a handle for a degrader.
• The E3 ligand is the moiety that recruits the ubiquitin ligase. The chemistry available here is the field’s main constraint, and it is the focus of much of this article.
• The linker connects the two ligands. Linker length, rigidity, and attachment geometry are not trivial spacers. They determine whether the target and ligase can adopt a productive orientation, and they have a strong influence on potency, selectivity, and drug-like properties [2].

The decisive event in PROTAC action is the formation of a ternary complex: target protein, PROTAC, and E3 ligase bound together as one assembly. How well that complex forms, rather than how tightly the PROTAC binds either partner on its own, governs how efficiently the target is ubiquitinated.

The point was made concrete by a crystal structure of the BRD4 degrader MZ1 bound to the E3 ligase VHL and a BRD4 bromodomain. It showed that the most effective degraders induce favourable, direct contacts between the target and the ligase, a phenomenon known as positive cooperativity [5]. Cooperativity helps explain why a PROTAC can degrade one member of a protein family while sparing close relatives, and why structure-guided design of the ternary complex can produce very high selectivity [5].

MZ1 and the phthalimide-based degrader dBET1 were among the first drug-like small-molecule PROTACs shown to work in cells. Both degraded BRD4, one by recruiting VHL and the other cereblon (CRBN), and together they moved the modality away from the peptide-based recruiters used in the earliest work [3][4].

The human genome encodes more than 600 E3 ligases, each evolved to recognise particular substrates in particular cellular contexts. Some are broadly expressed. Others are restricted to specific tissues, cell states, or subcellular compartments.

In principle that diversity is useful to drug developers. A ligase with restricted expression could, if it could be recruited, enable a degrader that acts only where that ligase is present, sparing healthy tissue. In practice, almost none of this diversity has been accessed [6].

A handful of E3 ligases account for the overwhelming majority of PROTACs reported so far. Cereblon (CRBN) and von Hippel–Lindau (VHL) are by far the most widely used, for one reason: high-quality, drug-like small-molecule ligands exist for both.

CRBN recruitment exploits the thalidomide class of immunomodulatory drugs, whose binding to CRBN provided the chemistry behind the first practical small-molecule degraders [3]. VHL ligands came out of dedicated medicinal chemistry and underpin many of the best-characterised degraders, including the cooperative BRD4 degraders described above [4][5][7].

Two other ligases, the inhibitor-of-apoptosis proteins (IAPs) and MDM2, have also been recruited, but far less often. The result is a field that has shown considerable breadth in what it can degrade while drawing on a strikingly narrow set of ligases [6][7].

Table 2.The E3 ligases most used in targeted protein degradation.

Fewer than ten of the more than 600 human E3 ligases have been used for degradation to date [6][7].

Of more than 600 human E3 ligases, fewer than ten have been used for targeted protein degradation, and most disclosed PROTACs rely on CRBN or VHL [6]. That concentration does not mean CRBN and VHL are the right choice for every job. It reflects where ligand chemistry happens to exist.

Depending on so few ligases carries real liabilities. Resistance can emerge when tumour cells downregulate or mutate the recruited ligase. Some targets are degraded poorly by CRBN or VHL simply because a productive ternary complex cannot form. And tissue-restricted degradation, one of the modality’s more attractive theoretical advantages, stays out of reach because the relevant ligases have no ligands. Expanding the repertoire of usable E3 ligases is widely treated as one of the most important open problems in the field [6][7].

The prize here is precision. If a ligase expressed predominantly in a particular tumour type or tissue could be recruited, a degrader built on that ligase would in principle act selectively in disease-relevant cells and leave the rest of the body largely alone. That is a built-in therapeutic window of a kind occupancy-based drugs rarely achieve [2][6].

Getting there depends on one thing above all: ligands that bind new E3 ligases. Which turns a biology problem into a hit-discovery problem – a problem Vipergen’s DNA-encoded library platform is built to solve.

If new E3 ligases are so desirable, why has the toolbox stayed so small? Several reasons.

Many E3 ligases lack obvious, well-formed small-molecule pockets, which makes them hard to drug by design. Others are difficult to express and purify in functional form, which frustrates conventional biochemical screening. And the historical E3 ligands were largely found by accident rather than by deliberate search. The CRBN-binding activity of thalidomide-class drugs, for example, was uncovered long after those drugs were already in clinical use [7].

Finding ligands for a chosen E3 ligase on purpose, rather than stumbling across them, calls for screening methods that can put enormous chemical diversity in front of difficult proteins.

The field has tried several routes. Covalent and electrophilic fragment screening has identified reactive ligands for ligases such as DCAF16 and RNF114. Structure-based design has been applied where structural information exists. Molecular-glue discovery campaigns have surfaced compounds that recruit ligases such as DCAF15 [7].

Each approach has extended the map, and each has limits. Covalent strategies depend on a suitably positioned reactive residue. Structure-based design needs a tractable structure. Traditional high-throughput screening samples only a modest slice of chemical space and often struggles with proteins that resist purification or immobilisation [7][8].

Table 3. Approaches to E3 ligase ligand discovery

DNA-encoded library screening changes both the scale and the logistics of ligand discovery. In a DEL, each small molecule is covalently linked to a unique DNA barcode recording its synthetic history. Because every compound’s identity is encoded in DNA, hundreds of millions to billions of distinct molecules can be pooled and screened together in a single tube, with binders identified by next-generation sequencing of the recovered barcodes.

This allows sampling of chemical space several orders of magnitude deeper than conventional high-throughput screening, at a fraction of the material cost [8]. For a problem defined by the scarcity of ligands against difficult proteins, depth of sampling is the relevant variable.

Library quality matters as much as library size.  Vipergen’s YoctoReactor (yR) technology synthesises DELs through DNA self-assembly that brings building blocks into proximity within a three-dimensional DNA junction. The design produces a one-to-one correspondence between each barcode and the small molecule it encodes, which suppresses false positives and simplifies resynthesis of confirmed hits off DNA [9][10]. Screening is then performed by Vipergen’s Binder Trap Enrichment (BTE), a homogeneous, solution-phase selection method that captures binding pairs without immobilising the target on a surface, avoiding the matrix and surface artefacts that complicate many affinity-based screens [9][10].

In short, Vipergen pairs deep, high-fidelity libraries with artefact-resistant selection to address the central task of E3 ligand discovery: finding genuine, developable binders for ligases that have resisted other methods.

A large share of disease-driving proteins are intrinsically disordered. They do not fold into a single stable three-dimensional structure but exist as dynamic ensembles of interconverting conformations.

Intrinsically disordered proteins and regions make up roughly a third of the human proteome and have central roles in signalling, transcription, and condensate formation. A recent computational study generated conformational ensembles for more than 28,000 disordered regions across the human proteome, which gives some sense of both their prevalence and their structural complexity [12]. Because they lack the deep, persistent pockets inhibitors require, disordered proteins have historically been labelled undruggable and remain one of the harder frontiers in drug discovery [11].

Targeted protein degradation offers a way around the impasse. A degrader does not have to occupy a functional site or lock a protein into an inactive conformation. It needs a ligand that binds the target well enough to form a productive ternary complex with an E3 ligase. A transient or shallow binding event that would be useless for inhibition can be enough to mark a disordered protein for destruction.

The bottleneck, again, is finding a binder at all, which returns the problem to hit discovery against a protein that may have no obvious druggable surface [11].

DEL selection does not depend on a target having a classical pocket. It asks only whether any molecule in a very large library binds somewhere on the protein with useful affinity and specificity. By sampling chemical space far more deeply than conventional screens, a high-quality DEL improves the odds of finding a usable binding handle on a protein that structure-based or fragment methods would write off [8][9]. For disordered proteins and other unconventional target classes, finding a handle where none was thought to exist is the prerequisite for building a degrader at all.

Disordered and unstable proteins pose a second, more practical obstacle: many cannot be readily produced as purified, well-behaved material for in-vitro screening.

Vipergen’s Cellular Binder Trap Enrichment (cBTE) addresses this by performing DEL selection inside living cells, which removes the requirement for a purified or immobilised target and allows screening against target classes that are otherwise difficult to handle, in a more physiologically relevant setting [10]. For a protein that refuses to behave in a test tube but is present in its native context inside a cell, in-cell selection sidesteps the problem that has blocked conventional approaches.

The same logic that makes DEL attractive for new E3 ligands, namely depth of sampling plus artefact-resistant selection with low protein requirements, applies equally to the targets on the other end of the PROTAC.

Oncology has been the proving ground for targeted protein degradation, and the modality has now cleared its most important hurdle: regulatory approval.

Vepdegestrant (ARV-471), an orally administered PROTAC that degrades the estrogen receptor, was compared with the established endocrine therapy fulvestrant in the Phase 3 VERITAC-2 trial (NCT05654623) in patients with ER-positive, HER2-negative advanced breast cancer whose disease had progressed after a CDK4/6 inhibitor and endocrine therapy [13]. Progression-free survival was assessed as a primary endpoint in two populations: the intention-to-treat population and the ESR1-mutant population. In March 2025 the sponsors reported that the trial met its primary endpoint in the ESR1-mutant population, with a statistically significant improvement in progression-free survival over fulvestrant. This was the first time a PROTAC degrader had shown clinical benefit in a Phase 3 setting. The trial did not meet the endpoint in the intention-to-treat population [14].

On 1 May 2026 the FDA approved vepdegestrant (marketed as Veppanu) for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy, alongside a companion diagnostic, Guardant360 CDx,  to identify ESR1 mutations [15]. It is the first PROTAC of any kind to reach approval [16].

That result moves targeted protein degradation from a promising laboratory concept to a clinically validated therapeutic strategy, and it has sharpened interest in extending degraders beyond oncology into immunology, inflammation, and neurodegeneration [2].

The case for degraders over inhibitors is strongest exactly where inhibitors are weakest. Inhibitors need a high-affinity, functionally important pocket, and they generally have to maintain near-complete target occupancy to be effective. Degraders need a binding handle, act catalytically, and remove the whole protein, scaffolding functions included, at sub-stoichiometric drug levels [2]. They can also address some resistance mechanisms that defeat inhibitors. (See Table 1 for a side-by-side comparison.)

None of this makes inhibitors obsolete. For many targets, a well-behaved active site is still the most direct route to a drug. But for transcription factors, scaffolding proteins, and disordered targets that have frustrated occupancy-based chemistry for decades, degradation is a real alternative [2][11].

The trajectory of the field keeps pointing at the same requirement. Clinical validation will drive expansion into new targets and new diseases. That expansion will mean degrading proteins CRBN and VHL handle poorly. And that needs both new E3 ligase ligands and binding handles on previously intractable targets [6][7][11].

Both are hit-discovery problems on difficult proteins – problems Vipergen’s DEL technologies are designed to address. As the set of usable ligases grows, so does the prospect of tissue- and disease-selective degraders with wider therapeutic windows, and of degraders aimed at the disordered proteome that conventional medicinal chemistry has not been able to reach.

1. Sakamoto K. M., Kim K. B., Kumagai A., Mercurio F., Crews C. M., Deshaies R. J. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U.S.A. (2001), 98(15), 8554–8559. DOI: 10.1073/pnas.141230798. https://www.pnas.org/doi/10.1073/pnas.141230798
2. Békés M., Langley D. R., Crews C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. (2022), 21(3), 181–200. DOI: 10.1038/s41573-021-00371-6. https://www.nature.com/articles/s41573-021-00371-6
3. Winter G. E., Buckley D. L., Paulk J., Roberts J. M., Souza A., Dhe-Paganon S., Bradner J. E. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science (2015), 348(6241), 1376–1381. DOI: 10.1126/science.aab1433. https://www.science.org/doi/10.1126/science.aab1433
4. Zengerle M., Chan K.-H., Ciulli A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. (2015), 10(8), 1770–1777. DOI: 10.1021/acschembio.5b00216. https://pubs.acs.org/doi/10.1021/acschembio.5b00216
5. Gadd M. S., Testa A., Lucas X., Chan K.-H., Chen W., Lamont D. J., Zengerle M., Ciulli A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. (2017), 13(5), 514–521. DOI: 10.1038/nchembio.2329. https://www.nature.com/articles/nchembio.2329
6. Schapira M., Calabrese M. F., Bullock A. N., Crews C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. (2019), 18(12), 949–963. DOI: 10.1038/s41573-019-0047-y. https://www.nature.com/articles/s41573-019-0047-y
7. Ishida T., Ciulli A. E3 ligase ligands for PROTACs: how they were found and how to discover new ones. SLAS Discov. (2021), 26(4), 484–502. DOI: 10.1177/2472555220965528. https://journals.sagepub.com/doi/full/10.1177/2472555220965528
8. Goodnow R. A. Jr., Dumelin C. E., Keefe A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discov. (2017), 16(2), 131–147. DOI: 10.1038/nrd.2016.213. https://www.nature.com/articles/nrd.2016.213
9. Blakskjaer P., Heitner T., Hansen N. J. V. Fidelity by design: Yoctoreactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery. Curr. Opin. Chem. Biol. (2015), 26, 62–71. DOI: 10.1016/j.cbpa.2015.02.003. https://doi.org/10.1016/j.cbpa.2015.02.003
10. Vipergen ApS. Technology: YoctoReactor (yR), Binder Trap Enrichment (BTE) and Cellular Binder Trap Enrichment (cBTE). https://www.vipergen.com/technology/
11. Lazar T., Connor A., DeLisle C. F., Burger V., Tompa P. Targeting protein disorder: the next hurdle in drug discovery. Nat. Rev. Drug Discov. (2025), 24(10), 743–763. DOI: 10.1038/s41573-025-01220-6. https://www.nature.com/articles/s41573-025-01220-6
12. Tesei G., Trolle A. I., Jonsson N., Betz J., Knudsen F. E., Pesce F., Johansson K. E., Lindorff-Larsen K. Conformational ensembles of the human intrinsically disordered proteome. Nature (2024), 626(8000), 897–904. DOI: 10.1038/s41586-023-07004-5. https://www.nature.com/articles/s41586-023-07004-5
13. Hamilton E. P., Ma C., De Laurentiis M., Iwata H., Hurvitz S. A., Wander S. A., Danso M., Lu D. R., Perkins Smith J., Liu Y., Tran L., Anderson S., Campone M. VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer. Future Oncol. (2024), 20(32), 2447–2455. DOI: 10.1080/14796694.2024.2377530. https://doi.org/10.1080/14796694.2024.2377530
14. Arvinas, Inc. and Pfizer Inc. Arvinas and Pfizer announce positive topline results from Phase 3 VERITAC-2 clinical trial (press release, 11 March 2025). https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-positive-topline-results-phase-3
15. U.S. Food and Drug Administration. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (1 May 2026). https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
16. Arvinas, Inc. Arvinas announces FDA approval of VEPPANU (vepdegestrant) for the treatment of ESR1m, ER+/HER2- advanced breast cancer (press release, 1 May 2026). https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-fda-approval-veppanu-vepdegestrant-treatment

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Figure: Conceptual overview of spatial pharmacology. Spatial pharmacology designs therapeutics based on intracellular location and cellular architecture. Organelle-targeted therapeutics direct drugs to specific compartments such as mitochondria or lysosomes. Protein relocalization strategies move proteins to alternative cellular locations to alter function. Condensate-targeting approaches exploit biomolecular phase separation to concentrate drugs within transcriptional or signaling condensates. Phase-separation therapeutics modulate the formation or stability of these condensates to influence disease pathways.

For most of modern drug discovery, success has been defined by affinity, potency, and selectivity at the molecular level. A compound binds a protein, inhibits an enzyme, blocks a receptor. But cells are not homogeneous reaction vessels. They are spatially organized systems composed of:

• Membrane-bound organelles
• Dynamic trafficking networks
• Phase-separated condensates
• Compartment-specific microenvironments

A molecule’s biological effect depends not only on what it binds — but where it goes.

Spatial pharmacology represents a paradigm shift: therapeutics are designed with intracellular geography in mind. Instead of merely targeting a protein, drugs can:

• Relocalize proteins to different organelles
• Partition selectively into biomolecular condensates
• Exploit phase separation dynamics
• Engage bacterial or mitochondrial proteostasis machinery
• Alter the spatial context of signaling networks

This emerging field encompasses:

• Organelle-targeted therapeutics
• Protein relocalization strategies
• Condensate-mediated drug discovery
• Phase separation therapeutics
• Spatially restricted proteolysis systems

As our understanding of cellular architecture deepens, spatial control is becoming a new axis of drug design.

Cells compartmentalize reactions to:

• Increase efficiency
• Prevent crosstalk
• Protect genomic integrity
• Regulate signaling thresholds

Key compartments include:

• Nucleus
• Mitochondria
• Endoplasmic reticulum
• Lysosomes
• Endosomes
• Peroxisomes

Additionally, cells contain membraneless organelles, formed via liquid–liquid phase separation (LLPS). These condensates concentrate proteins and RNA into dynamic microdomains.

Drugs that ignore this spatial complexity may:

• Fail to reach their intended microenvironment
• Be sequestered away from targets
• Disrupt unintended compartments

Spatial pharmacology embraces compartmentalization as a design principle rather than a pharmacokinetic obstacle.

Organelle-targeted therapeutics aim to direct molecules — or target proteins themselves — to specific intracellular locations.

Certain chemical motifs preferentially accumulate in specific organelles. For example:

• Lipophilic cations accumulate in mitochondria
• Acidic compartments trap weak bases
• Nuclear localization sequences direct nuclear import

By engineering compounds with organelle-targeting elements, researchers can:

• Enhance local concentration
• Improve target engagement
• Reduce systemic toxicity

Beyond delivering drugs to organelles, another strategy is to move proteins themselves.

Small molecules or bifunctional chimeras can bind a protein of interest and tether it to:

• A mitochondrial membrane
• A nuclear export receptor
• A lysosomal surface
• A cytoskeletal anchor

Relocalization can:

• Inactivate signaling pathways
• Prevent nuclear transcriptional activity
• Induce degradation through organelle-associated mechanisms
• Alter metabolic flux

This represents functional knockdown without necessarily degrading the protein.

Mitochondria are central to:

• Energy metabolism
• Apoptosis regulation
• Reactive oxygen species production

Organelle-targeted therapeutics in oncology may:

• Induce mitochondrial stress
• Sensitize cells to apoptosis
• Exploit tumor metabolic rewiring

Conversely, in neurodegeneration, mitochondrial targeting can:

• Reduce oxidative stress
• Restore bioenergetic balance

Spatial precision improves therapeutic index.

One of the most transformative developments in cell biology over the past decade is the discovery of biomolecular condensates.

Condensates are membraneless compartments formed through liquid–liquid phase separation (LLPS). They arise when multivalent interactions among proteins and RNA cause demixing from the surrounding cytoplasm or nucleoplasm.

Examples include:

• Nucleoli
• Stress granules
• P-bodies
• Transcriptional super-enhancer condensates
• DNA damage foci

These structures concentrate specific biomolecules while excluding others.

Condensates influence:

• Gene transcription
• RNA processing
• Signal transduction
• Stress responses
• DNA repair

Drugs can:

• Partition preferentially into condensates
• Alter phase separation dynamics
• Disrupt scaffold-client interactions
• Stabilize or dissolve condensates

Thus, drug behavior is not solely defined by binding affinity — but by partitioning behavior within mesoscale cellular structures.

Certain small molecules concentrate within condensates due to:

• Electrostatic interactions
• π–π stacking
• Intrinsically disordered region (IDR) affinity
• RNA binding properties

Partitioning can amplify local drug concentration beyond cytoplasmic levels. However, it can also:

• Sequester drugs away from intended targets
• Create off-target effects within transcriptional hubs

Understanding condensate partition coefficients is becoming a critical parameter in medicinal chemistry.

Phase separation therapeutics aim to:

• Dissolve oncogenic transcriptional condensates
• Stabilize protective condensates
• Prevent pathological aggregation

In oncology, super-enhancer condensates regulate oncogene expression. Disrupting their integrity can suppress transcriptional addiction.

In neurodegeneration, aberrant phase transitions may drive toxic aggregation. Modulating condensate fluidity could prevent pathological conversion.

Modern screening approaches include:

• In vitro reconstitution of phase separation
• High-content live-cell imaging
• Fluorescence recovery after photobleaching (FRAP)
• Quantitative partitioning assays

Drug discovery is evolving from simple binding assays to mesoscale biophysical profiling.

Spatial pharmacology extends beyond eukaryotic organelles.

BacPROTACs adapt induced proximity logic to bacterial proteostasis machinery. Rather than recruiting human E3 ligases, BacPROTACs engage bacterial proteases such as Clp systems.

• Novel antibacterial strategies
• Targeted degradation of resistance factors
• Reduced reliance on enzyme inhibition

Bacterial cells lack compartmental complexity comparable to eukaryotes, but spatial organization of proteases still governs degradation efficiency.

Spatial pharmacology requires new design principles.

Beyond plasma concentration, developers must assess:

• Nuclear accumulation
• Mitochondrial enrichment
• Lysosomal sequestration
• Condensate partitioning

Advanced imaging techniques now quantify intracellular distribution at high resolution.

Physicochemical parameters influence spatial behavior:

• Charge
• Lipophilicity
• Polar surface area
• Hydrogen bonding capacity

Medicinal chemists must balance permeability with compartment selectivity.

Spatial localization is dynamic. Stress, cell cycle stage, and signaling events alter compartment architecture.

A drug may behave differently in:

• Hypoxic tumors
• Neurons vs hepatocytes
• Inflamed tissues

Time-resolved spatial profiling becomes essential.

Cancer cells often reorganize spatial architecture:

• Super-enhancer condensates drive oncogene transcription
• DNA repair condensates maintain genomic instability
• Metabolic enzymes relocalize under stress

Spatial pharmacology strategies may:

• Disrupt transcriptional condensates
• Relocalize oncogenic proteins
• Target mitochondrial vulnerabilities

Many neurodegenerative diseases involve:

• Protein aggregation
• Stress granule dysfunction
• Aberrant phase transitions

Condensate drug discovery may prevent pathological solidification of liquid compartments.

Organelle-targeted therapeutics may protect:

• Mitochondria
• Lysosomes
• Synaptic compartments

Pathogens manipulate host spatial organization:

• Viral replication factories
• Bacterial inclusion bodies

Spatially aware drugs could disrupt these specialized compartments.

Organelle dysfunction underlies:

• Mitochondrial disorders
• Lysosomal storage diseases
• Peroxisomal disorders

Targeted delivery to affected organelles may improve therapeutic efficacy.

Cells adapt spatial architecture under drug pressure. Potential resistance mechanisms include:

• Condensate remodeling
• Organelle biogenesis changes
• Compensatory trafficking pathways
• Altered partitioning behavior

Understanding spatial plasticity is critical for durable therapy.

Spatial pharmacology intersects with:

• Targeted protein degradation
• Synthetic lethality
• RNA-targeted therapeutics
• Immunotherapy

For example:

• Degraders may preferentially act within condensates
• Synthetic lethal vulnerabilities may arise from organelle stress
• RNA-targeted drugs may accumulate in nuclear condensates

Future therapeutics may combine spatial targeting with induced proximity.

Advances in machine learning enable:

• Prediction of phase separation propensity
• Modeling of drug partition coefficients
• Simulation of organelle localization
• Integration of multi-omic spatial datasets

Computational spatial pharmacology may soon guide medicinal chemistry from the earliest stages.

Biotech innovation in spatial pharmacology is accelerating. Emerging companies focus on:

• Condensate-disrupting compounds
• Organelle-targeted degraders
• Spatially restricted proteostasis modulation
• Mesoscale screening platforms

Pharmaceutical interest is rising because:

• Spatial targeting expands the druggable proteome
• Novel mechanisms create differentiation
• Biomolecular condensates represent underexploited targets

The next frontier may include:

• Multi-compartment targeting chimeras
• Programmable relocalization systems
• Condensate-selective degraders
• Organelle-specific E3 ligase atlases
• Spatially resolved precision oncology

As spatial multi-omics advances, vulnerability maps may include not just gene expression — but subcellular context.

Traditional pharmacology operates in two dimensions:

• Molecular affinity
• Target selectivity

Spatial pharmacology introduces the third:

• Intracellular location

Organelle-targeted therapeutics and condensate-mediated drug discovery redefine what it means to engage a target. The effectiveness of a drug may depend not only on binding strength, but on its ability to navigate cellular geography.

By integrating knowledge of:

• Organelle biology
• Phase separation
• Intracellular trafficking
• Mesoscale organization

drug discovery becomes not just chemistry and biology — but cellular architecture engineering.

The future of medicine may hinge on mastering this spatial dimension. In the coming decade, spatial pharmacology is poised to transform how we conceptualize therapeutic intervention — from blocking molecular function to orchestrating cellular organization itself.

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Figure: Evolution of induced proximity therapeutics beyond classical PROTACs. Classical PROTACs recruit an E3 ubiquitin ligase to a target protein to induce degradation. Next-generation modalities expand this principle: RIPTACs create context-dependent proximity for tumor-selective lethality; DUBTACs stabilize proteins by recruiting deubiquitinases; PHOTACs and pcPROTACs enable light-controlled degradation; VIPER-TACs leverage viral ligases to broaden substrate scope; and PROxAb systems use antibody delivery to achieve cell-type-specific degrader activation.

Targeted protein degradation (TPD) has reshaped modern drug discovery by shifting the paradigm from occupancy-driven pharmacology to event-driven pharmacology. Rather than inhibiting protein function through sustained binding, degraders trigger the removal of disease-driving proteins from the cell entirely. This catalytic mode of action enables suppression of scaffolding proteins, transcription factors, and other historically “undruggable” targets.

First-generation PROTACs (proteolysis-targeting chimeras) demonstrated that small molecules can recruit E3 ubiquitin ligases to a target protein, inducing ubiquitination and proteasomal degradation. Clinical progress in oncology validated the approach. However, the field has rapidly evolved beyond classical PROTAC architectures.

Today’s next-generation modalities expand induced proximity in multiple dimensions:

• Context-dependent proximity (RIPTACs)
• Targeted protein stabilization (DUBTACs)
• Light-controlled degraders (PHOTACs, pcPROTACs)
• Virus-inspired proximity systems (VIPER-TACs)
• Antibody-delivered degraders (PROxAb)

Collectively, these approaches redefine TPD as a broader class of induced proximity therapeutics. The future is no longer just about degradation — it is about programmable control of protein fate, function, and location.

Traditional small molecules rely on occupancy: a drug must remain bound to exert effect. In contrast, degraders operate catalytically. Once a target is ubiquitinated and committed to degradation, the degrader molecule can, in principle, dissociate and engage another copy of the protein.

This creates several advantages:

• Reduced dependence on high-affinity binding
• Ability to eliminate scaffolding functions
• Suppression of both enzymatic and non-enzymatic activity
• Potential to overcome resistance mutations

At the core of TPD is induced proximity — the deliberate forced interaction between two proteins that would not normally engage. In classical PROTACs, the two components are:

1. The target protein
2. An E3 ubiquitin ligase

A heterobifunctional molecule brings them together, forming a ternary complex that drives ubiquitination.

However, induced proximity is not limited to E3 ligases or degradation. The same logic can recruit:

• Deubiquitinases
• Kinases
• Autophagy initiators
• RNases
• Viral ligases
• Conditional control elements

This conceptual shift is what defines the next wave of innovation.

Regulated Induced Proximity Targeting Chimeras (RIPTACs) extend the logic of proximity to create tumor-selective lethality without necessarily degrading the target.

RIPTACs bind:

• A broadly expressed essential protein
• A tumor-restricted or overexpressed protein

By forcing proximity, the essential protein becomes functionally inactivated — but only in cells expressing the tumor-specific partner. This produces synthetic-lethal-like selectivity without directly targeting mutated genes.

Many essential proteins are poor therapeutic targets due to systemic toxicity. RIPTACs introduce a spatial and contextual filter: only cells co-expressing both proteins are affected.

This approach offers:

• Precision oncology selectivity
• Potential activity against non-mutated drivers
• Reduced reliance on enzymatic inhibition

• Identifying suitable tumor-restricted anchors
• Avoiding off-tumor expression
• Managing adaptive rewiring

RIPTACs illustrate how induced proximity can move beyond degradation into conditional functional rewiring.

While most proximity-based drugs remove proteins, DUBTACs (Deubiquitinase-Targeting Chimeras) reverse this logic.

DUBTACs recruit a deubiquitinase (DUB) to a ubiquitinated target protein. This removes ubiquitin chains and rescues the protein from degradation.

Many diseases arise from insufficient protein levels:

• Tumor suppressor loss
• Haploinsufficiency disorders
• Misfolding-related degradation

Instead of inhibiting E3 ligases globally (which risks toxicity), DUBTACs localize deubiquitination to a specific protein.

• Stabilizing mutant but functional tumor suppressors
• Correcting degradation-prone variants
• Potential rare disease interventions

• DUB selectivity and off-target deubiquitination
• Achieving productive ternary complexes
• Avoiding interference with endogenous ubiquitin signaling

DUBTACs demonstrate that induced proximity is not inherently degradative — it can restore function.

Precision control is an emerging frontier. Light-responsive degraders introduce temporal and spatial specificity.

PHOTACs incorporate photoswitchable moieties (e.g., azobenzene-like systems) that toggle between active and inactive conformations upon light exposure.

This allows:

• Reversible activation
• Localized degradation
• Dynamic pathway interrogation

Potential applications include neuroscience and developmental biology, where temporal control is critical.

Photocaged PROTACs remain inactive until light exposure removes a blocking group. Unlike PHOTACs, activation is typically irreversible.

• Clean on/off state
• Reduced systemic activity
• High spatiotemporal precision

These systems extend light control beyond degradation into proximity-driven signaling or reversible protein complex formation.

Rather than simply removing proteins, they allow:

• Light-triggered protein assembly
• Signal rewiring
• Controlled functional modulation

Collectively, these technologies move TPD toward precision pharmacology.

Viruses encode E3 ligases and hijack host ubiquitin systems to eliminate immune regulators. VIPER-TAC strategies leverage viral ligase logic to expand the degrader toolbox.

• Distinct substrate preferences
• Unique regulatory interfaces
• Potential to target proteins inaccessible to canonical ligases

• Antiviral therapies
• Immune modulation
• Novel substrate scope expansion

The challenge lies in specificity and safety — viral machinery must be carefully engineered to avoid unintended degradation.

One of the major limitations of small-molecule degraders is systemic exposure and tissue distribution. PROxAb platforms combine:

• Targeting antibodies
• Cleavable linkers
• Intracellular degrader payloads

1. Antibody binds a cell-surface antigen
2. Complex internalizes
3. Linker cleaves intracellularly
4. Released PROTAC engages intracellular target

This approach mirrors antibody-drug conjugates (ADCs), but instead of cytotoxic payloads, the cargo is a degrader.

• Cell-type specificity
• Reduced systemic toxicity
• Expanded therapeutic window

• Endosomal escape efficiency
• Linker stability
• Drug-to-antibody ratio optimization

PROxAb represents convergence between biologics and TPD.

Despite architectural diversity, common design rules apply.

Productive proximity requires:

• Favorable protein-protein interactions
• Proper geometry
• Dynamic stability

Cooperative ternary complex formation often predicts degradation efficiency better than binary binding affinity.

Choice of recruited partner dictates:

• Tissue specificity
• Resistance pathways
• Safety profile

Emerging strategies expand beyond CRBN and VHL to tissue-restricted ligases.

Linkers determine:

• Flexibility vs rigidity
• Orientation of interacting surfaces
• Cellular permeability

Structure-guided design and AI modeling increasingly guide optimization.

Next-generation systems incorporate:

• Tumor-restricted expression
• Light activation
• Antibody delivery
• Conditional engagement

Selectivity is shifting from binding specificity to biological context specificity.

Targeted protein degradation has moved from conceptual novelty to clinical reality, particularly in oncology. Next-generation modalities aim to address:

• Solid tumor resistance
• Central nervous system delivery
• Rare genetic disorders
• Immune modulation

Several biotech companies are now expanding pipelines into:

• Tissue-restricted ligase discovery
• Autophagy-based degradation
• RNA-targeted proximity systems

As the field matures, differentiation increasingly depends on:

• Ligase access
• Conditional control
• Safety margins
• Novel substrate space

Resistance mechanisms include:

• E3 ligase downregulation
• Target mutation
• Adaptive rewiring
• Proteostasis compensation

Next-generation platforms attempt to preempt resistance through:

• Alternative ligases
• Conditional activation
• Multi-target strategies

Combinatorial proximity drugs may represent a future frontier.

The evolution of targeted protein degradation reveals a broader principle: drug discovery is becoming programmable biology.

Future directions include:

• Multi-functional chimeras that degrade one protein while stabilizing another
• Tissue-restricted ligase atlases
• AI-designed ternary complexes
• Integration with synthetic lethality frameworks
• Expansion beyond proteins to RNA and chromatin complexes

Ultimately, induced proximity is not a single modality — it is a design philosophy.

The next decade will likely see:

• More precise control
• Broader target classes
• Increased integration with biologics
• Spatial and temporal programmability

Targeted protein degradation began as a clever workaround for undruggable proteins. It is now evolving into a foundational technology platform capable of reshaping therapeutic intervention at a systems level.

The era beyond classical PROTACs has begun — and it is defined not by degradation alone, but by the controlled orchestration of molecular proximity.

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Figure: Conceptual model of synthetic lethality in cancer therapy. In normal cells, redundant pathways allow survival when either gene is inhibited. In cancer cells, mutation of one gene creates dependency on a compensatory pathway. Targeting this remaining pathway produces synthetic lethality, selectively killing tumor cells while sparing normal tissue. Clinically relevant examples include WRN inhibition in MSI-high tumors and PRMT5 targeting in MTAP-deleted cancers.

For decades, oncology drug discovery focused on inhibiting activated oncogenes — mutant kinases, amplified receptors, dysregulated signaling enzymes. While transformative in many cases, this strategy has intrinsic limits:

• Not all cancers harbor targetable oncogenic mutations
• Many driver proteins lack druggable pockets
• Tumors evolve resistance through pathway rewiring

Synthetic lethality offers a fundamentally different approach. Instead of directly targeting the mutation, it exploits context-specific dependencies created by that mutation.

In simple terms: two genes are synthetically lethal if loss of either alone is tolerated, but loss of both is lethal.

Cancer cells, by virtue of their mutations, often become dependent on backup pathways that normal cells do not require. Synthetic lethality drug discovery aims to identify and therapeutically exploit these vulnerabilities.

The modern era of synthetic lethality encompasses:

• Genome-scale CRISPR screening
• Context-dependent essentiality mapping
• Precision biomarker-driven trials
• Integration with induced proximity therapeutics

Key exemplars include:

• WRN inhibitors in MSI-high cancers
• PRMT5 targeting in MTAP-deleted tumors
• Context-dependent induced proximity strategies

This pillar article explores how synthetic lethality is reshaping precision oncology.

The concept of synthetic lethality originated in classical genetics. In model organisms, researchers observed that deletion of either Gene A or Gene B was tolerated, but deletion of both caused death.

In cancer biology, the idea became clinically validated with PARP inhibitors in BRCA-mutated tumors — demonstrating that therapeutic synthetic lethality could be achieved in patients.

This success shifted oncology strategy from:

• “Target the mutation”

to:

• “Target what the mutation makes essential.”

Feasibility study: 2-4 weeks
Screening: 4-8 weeks

Cancer cells accumulate:

• DNA repair defects
• Replication stress
• Metabolic rewiring
• Proteotoxic stress
• Chromosomal instability

These alterations create dependencies on compensatory pathways. While normal cells retain redundancy, tumor cells often operate at the edge of viability.

Synthetic lethality drug discovery aims to identify these edge conditions.

Modern synthetic lethality relies heavily on:

• CRISPR knockout screens
• RNAi dependency maps
• Multi-omic profiling
• Patient-derived models

Large-scale datasets now catalog gene essentiality across hundreds of cancer cell lines. These maps reveal:

• Lineage-specific vulnerabilities
• Mutation-specific dependencies
• Epigenetic context effects

The challenge lies in translating these genetic interactions into druggable targets with sufficient therapeutic windows.

One of the most compelling recent examples of synthetic lethality involves WRN helicase dependency in microsatellite instability-high (MSI-high) cancers. WRN plays a critical role in DNA replication and repair.

MSI-high cancers arise from mismatch repair (MMR) deficiency. Loss of MMR leads to:

• Accumulation of insertion/deletion mutations
• Replication stress
• DNA secondary structure instability

To survive this genomic instability, MSI-high tumor cells become dependent on WRN helicase activity.

WRN helps resolve:

• DNA secondary structures
• Replication fork stalling
• Microsatellite-induced instability

In MMR-deficient cells, unresolved structures accumulate rapidly without WRN, leading to:

• Chromosomal breakage
• Mitotic catastrophe
• Cell death

In contrast, normal MMR-proficient cells tolerate WRN inhibition more effectively.

WRN inhibitors represent a promising strategy in MSI-high colorectal, gastric, and endometrial cancers.

Advantages include:

• Strong genetic validation
• Biomarker clarity (MSI-high status)
• Potential synergy with immunotherapy

Challenges remain:

• Achieving selective helicase inhibition
• Avoiding toxicity in proliferative tissues
• Managing resistance through compensatory repair pathways

WRN inhibition exemplifies synthetic lethality driven by DNA repair deficiency.

Another well-characterized vulnerability involves PRMT5 inhibition in tumors with MTAP deletion. PRMT5 is an epigenetic regulator involved in symmetric arginine methylation. MTAP is frequently co-deleted with CDKN2A in many cancers.

MTAP deletion leads to accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5. This creates a state where:

• PRMT5 activity is already compromised
• Cancer cells operate near minimal PRMT5 function
• Further inhibition becomes selectively lethal

PRMT5 regulates:

• Splicing
• Chromatin modification
• Transcriptional control

MTAP-deleted cells are hypersensitive to PRMT5 inhibition because MTA accumulation lowers the functional threshold.

Therapeutic approaches include:

• Substrate-competitive inhibitors
• MTA-cooperative inhibitors
• Context-selective PRMT5 targeting

MTAP deletion is common across:

• Glioblastoma
• Pancreatic cancer
• Lung cancer
• Mesothelioma

This provides a broad patient population with defined biomarker stratification.

Key development challenges:

• Avoiding hematologic toxicity
• Optimizing therapeutic index
• Understanding splicing-related side effects

PRMT5–MTAP represents a metabolic-epigenetic synthetic lethal axis.

Beyond classical enzyme inhibition, induced proximity technologies are beginning to intersect with synthetic lethality strategies. RIPTACs represent one such example.

RIPTACs force interaction between:

• A broadly expressed essential protein
• A tumor-restricted protein

The essential protein becomes functionally impaired only in cells expressing the tumor-specific anchor. This creates synthetic lethality without directly targeting a mutated gene.

• Expanded druggable space
• Selectivity driven by co-expression
• Potential targeting of non-mutant tumors

Induced proximity adds a programmable dimension to synthetic lethality.

Genome-wide CRISPR knockout or CRISPR interference screens identify:

• Mutation-specific essential genes
• Pathway dependencies
• Synergistic vulnerabilities

High-throughput combinatorial screens accelerate mapping of lethal gene pairs.

Synthetic lethality is rarely binary. Context matters:

• Tumor lineage
• Epigenetic state
• Metabolic environment
• Microenvironmental stress

Integrating genomics, transcriptomics, proteomics, and metabolomics improves predictive accuracy.

Precision oncology vulnerabilities require robust biomarkers:

• MSI-high status for WRN
• MTAP deletion for PRMT5
• Specific mutation signatures

Without clear stratification, therapeutic windows collapse.

As with any targeted therapy, resistance can emerge. Common resistance pathways include:

• Restoration of lost repair functions
• Upregulation of compensatory pathways
• Mutation of drug target
• Epigenetic adaptation

For example:

• Alternative helicases may compensate for WRN inhibition
• PRMT5 pathway rewiring may restore splicing balance

Combination strategies are often necessary to sustain efficacy.

Synthetic lethality often synergizes with:

• Immunotherapy
• DNA-damaging agents
• Targeted protein degradation
• Epigenetic modulators

For example:

• WRN inhibition may increase tumor mutational burden and immune visibility
• PRMT5 inhibition may sensitize tumors to splicing stress

Rational combinations are critical for durable response.

Emerging directions include:

• Targeting replication stress pathways
• Exploiting metabolic bottlenecks
• Synthetic lethal interactions with chromatin remodelers
• Leveraging tumor microenvironment dependencies

AI-driven models may soon predict synthetic lethal interactions de novo.

Synthetic lethality drug discovery has become a cornerstone of precision oncology pipelines.

Pharmaceutical interest is high because:

• Genetic validation reduces target risk
• Biomarker-defined populations improve trial efficiency
• First-in-class opportunities are abundant

Companies are investing in:

• Dependency mapping platforms
• CRISPR-enabled discovery
• Computational vulnerability prediction

Synthetic lethality is now integrated into mainstream oncology R&D strategy.

The future of cancer therapy may depend less on targeting oncogenes directly and more on targeting what cancer cells cannot live without.

Synthetic lethality reframes cancer not as a disease of activation alone, but as a disease of vulnerability.

Key future developments may include:

• Personalized dependency maps
• Dynamic vulnerability profiling during treatment
• Synthetic lethal networks rather than single pairs
• Integration with spatial and proximity-based therapeutics

Precision oncology vulnerabilities are likely to become increasingly refined as tumor heterogeneity is better understood.

Synthetic lethality drug discovery represents one of the most rational and genetically grounded approaches in modern oncology.

From WRN inhibitors in MSI-high cancers to PRMT5 targeting in MTAP-deleted tumors, context-specific vulnerabilities are yielding actionable therapeutic strategies.

The core insight is simple but powerful: cancer cells survive by rewiring biology — and that rewiring creates dependencies.

By systematically identifying and exploiting those dependencies, precision oncology moves beyond inhibiting drivers to dismantling survival scaffolds.

As discovery technologies mature and induced proximity tools expand the targetable space, synthetic lethality will continue to redefine how cancer is treated — not by attacking what tumors are, but by exploiting what they cannot live without.

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Figure: Major strategies in RNA-targeted small-molecule therapeutics. RNA-targeted pharmacology acts upstream of protein synthesis. Splicing modifiers alter exon selection in pre-mRNA to reshape transcript isoforms. RIBOTACs recruit endogenous ribonucleases such as RNase L to selectively degrade disease-causing RNA transcripts. Ribosome-stalling small molecules bind within the ribosomal exit tunnel and arrest translation of specific nascent peptide sequences, suppressing protein production. Together these approaches expand drug discovery beyond proteins to the transcriptome.

For decades, small-molecule drug discovery has focused almost exclusively on proteins — particularly enzymes and receptors with well-defined binding pockets. Yet the human genome encodes far more RNA species than druggable proteins. Messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), microRNAs, repeat-expansion transcripts, and structured untranslated regions represent a vast and largely untapped regulatory landscape.

Recent advances in structural biology, RNA chemistry, and proximity-based pharmacology have catalyzed a new frontier: RNA-targeted small molecules and translation-modulating therapeutics.

Rather than inhibiting protein function after synthesis, these strategies act upstream by:

• Modulating pre-mRNA splicing
• Degrading disease-causing RNA selectively
• Arresting translation of specific nascent polypeptides
• Exploiting RNA structure as a druggable motif

The field now encompasses:

• Splicing-modifier therapeutics
• RIBOTACs
• Ribosome-stalling small molecules (“interdictors”)

Collectively, these approaches redefine small-molecule pharmacology — from targeting static proteins to dynamically regulating gene expression itself.

Many disease drivers are difficult to inhibit at the protein level:

• Transcription factors lacking enzymatic pockets
• Scaffolding proteins
• Gain-of-function mutations
• Proteins expressed at extremely high levels

Targeting RNA offers several advantages:

• Control before translation
• Access to noncoding regulatory molecules
• Potential for high selectivity via structural motifs
• Opportunity to eliminate toxic transcripts directly

Importantly, RNA structures are not random coils. Many RNAs fold into:

• Hairpins
• Bulges
• Internal loops
• G-quadruplexes
• Pseudoknots

These structural motifs create binding surfaces analogous to protein pockets.

Pre-mRNA splicing is a tightly regulated process that removes introns and joins exons. Errors in splicing contribute to:

• Cancer
• Neurodegeneration
• Genetic diseases

Small molecules can alter splice-site selection or spliceosome activity, shifting transcript isoforms in therapeutically beneficial ways.

Splicing modifiers typically interact with:

• Core spliceosome components
• RNA-protein interfaces
• Structured RNA motifs within pre-mRNA

These interactions alter exon inclusion or exclusion.

In oncology, mutations in splicing factors (e.g., SF3B1) create vulnerabilities. Cancer cells often operate near the threshold of splicing fidelity. Small perturbations can push them into transcriptomic catastrophe.

Cancer cells frequently harbor:

• Spliceosome mutations
• Elevated transcriptional stress
• Increased reliance on aberrant splicing programs

Splicing modifiers can:

• Induce exon skipping in oncogenic transcripts
• Create neoantigens
• Trigger apoptosis via splicing overload

This creates a therapeutic window distinct from normal cells.

Beyond oncology, splicing correction has proven transformative in inherited disorders where exon misselection drives pathology.

Small molecules offer advantages over antisense oligonucleotides:

• Oral bioavailability potential
• Broader tissue penetration
• Lower manufacturing complexity

However, transcriptome-wide effects remain a concern. Dose-dependent selectivity and careful biomarker development are critical.

RIBOTACs represent a catalytic approach to RNA elimination.

RIBOTACs are bifunctional small molecules that:

1. Bind a structured RNA target
2. Recruit an endogenous ribonuclease (often RNase L)

This induced proximity triggers selective cleavage of the target RNA.

Unlike antisense oligonucleotides (ASOs) or siRNA, RIBOTACs:

• Are small molecules
• Potentially cross membranes more efficiently
• Function catalytically
• Exploit endogenous RNase machinery

RNase L is normally activated in antiviral responses. RIBOTACs co-opt this system by tethering RNase L near a disease-relevant RNA.

Key design principles include:

• High-affinity RNA binding
• Minimal off-target RNase recruitment
• Proper geometric alignment
• Avoiding global RNase activation

The ternary complex — RNA + RIBOTAC + RNase — parallels PROTAC logic but in the RNA domain.

RIBOTACs may complement nucleic acid therapeutics rather than replace them.

Potential RNA targets include:

• Structured mRNAs
• Oncogenic lncRNAs
• Repeat expansion transcripts
• Viral RNAs

Structured motifs are particularly attractive because they create binding specificity.

While RIBOTACs eliminate RNA, ribosome-stalling molecules act during translation.

Selective ribosome-stalling compounds bind within the ribosomal exit tunnel and interact with specific nascent peptide sequences. This causes:

• Translational arrest
• Premature termination
• Reduced protein output

Importantly, stalling can be sequence-dependent, enabling selective targeting of specific proteins.

Traditional translation inhibitors (e.g., broad-spectrum antibiotics) globally suppress protein synthesis.

Ribosome-stalling therapeutics aim for:

• Target-selective arrest
• Reduced global toxicity
• Context-dependent effects

By recognizing specific amino acid motifs emerging from the ribosome, these compounds achieve precision.

Many oncogenic drivers are difficult to degrade post-translationally due to:

• High expression
• Rapid turnover
• Structural inaccessibility

Translation arrest offers an alternative:

• Suppress production at the source
• Reduce protein accumulation
• Potentially overcome degradation resistance

• Avoiding unintended translational stress responses
• Managing integrated stress pathway activation
• Ensuring sequence selectivity

High-resolution cryo-EM studies have been critical in elucidating binding mechanisms.

RNA structure is dynamic and context-dependent. Key tools include:

• SHAPE-MaP
• Cryo-EM
• NMR
• Chemical probing

Accurate structural models are essential for rational design.

RNA is chemically similar across transcripts. Selectivity arises from:

• Unique structural motifs
• Bulge geometry
• Base stacking interactions
• Minor groove architecture

Medicinal chemistry must account for:

• Electrostatic interactions
• Hydrogen bonding networks
• Conformational flexibility

Because many RNAs share structural features, off-target risks include:

• Unintended splicing shifts
• Degradation of essential transcripts
• Activation of innate immune pathways

High-throughput transcriptomic profiling is mandatory.

Like PROTACs, RIBOTACs depend on ternary complex formation. Design parameters include:

• Orientation constraints
• Flexible vs rigid linkers
• Enzyme recruitment efficiency
• Catalytic turnover

AI-driven modeling may soon enable predictive RNA–ligand–enzyme complex design.

RNA-targeted small molecules can:

• Suppress oncogenic splice variants
• Degrade oncogenic transcripts
• Arrest translation of driver proteins
• Exploit cancer-specific RNA dependencies

Tumors with splicing factor mutations are particularly vulnerable.

Diseases caused by toxic RNA repeats (e.g., CAG, CGG expansions) are prime candidates for RIBOTAC strategies.

Selective degradation of repeat-containing transcripts could:

• Reduce toxic RNA foci
• Decrease aberrant protein translation
• Modify disease course

Structured viral RNAs represent attractive targets:

• Conserved secondary structures
• Essential replication elements
• Reduced host homologs

RIBOTAC-like strategies could selectively degrade viral genomes.

RNA-binding proteins and aberrant RNA splicing are central to:

• ALS
• Frontotemporal dementia
• Huntington’s disease

Splicing correction and RNA degradation offer novel intervention points.

RNA-targeted approaches can synergize with:

• Targeted protein degradation
• Synthetic lethality strategies
• Immunotherapy
• Gene editing

For example:

• RNA suppression may sensitize tumors to degrader therapy
• Splicing modulation can create neoantigens for immune targeting

The therapeutic ecosystem is increasingly combinatorial.

RNA-targeted drug discovery is transitioning from exploratory chemistry to translational programs.

Key enabling factors:

• Improved RNA structural resolution
• Better predictive modeling
• Growing understanding of transcriptome dynamics

Investment interest reflects recognition that:

• RNA expands the druggable universe
• Structured RNAs provide specificity opportunities
• Small molecules offer advantages over nucleic acids in certain contexts

Companies are building pipelines around:

• Splicing modulation
• RNA degraders
• Translation regulators

As with protein-targeted drugs, resistance may arise via:

• RNA mutation altering structure
• Alternative splicing compensation
• Upregulation of parallel pathways
• Stress response activation

Combination therapies may mitigate resistance risk.

The next wave of innovation may include:

• Programmable RNA degraders
• Multi-functional RNA-binding chimeras
• Tissue-specific RNA targeting strategies
• AI-guided RNA structure prediction
• Condensate-aware RNA pharmacology

Advances in computational biology will likely accelerate identification of:

• Druggable RNA motifs
• Disease-specific transcript vulnerabilities
• RNA–protein interaction hotspots

RNA-targeted small molecules and translation-modulating therapeutics represent a fundamental expansion of drug discovery logic.

Rather than intervening after protein synthesis, these approaches act:

• At the transcript level
• During translation
• Within splicing regulation

They convert RNA from an informational intermediary into a direct pharmacological substrate.

As the field matures, RNA-targeted drug discovery may parallel — and in some cases surpass — protein-centric approaches in impact. Structured RNAs, inducible ribonuclease recruitment, and selective ribosome stalling collectively broaden the scope of what is therapeutically addressable.

The central dogma once defined biology as DNA → RNA → protein. Modern pharmacology increasingly operates upstream — at RNA — where disease signals originate.

The era of RNA-targeted small molecules has begun.

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Figure: Overview of lysosome- and autophagy-based targeted degradation technologies.
Lysosomal degradation pathways expand targeted protein degradation beyond the ubiquitin–proteasome system. LYTACs and PROTABs enable clearance of extracellular and membrane proteins through receptor-mediated endocytosis and lysosomal trafficking. Intracellular autophagy-based systems include ATTECs (LC3 tethering), AUTACs (K63-linked ubiquitin autophagy signaling), AUTOTACs (p62-mediated recruitment), and ULKTACs, which initiate autophagy through ULK1 activation. Together these technologies broaden the degradable target space to include extracellular proteins, aggregates, and organelles.

Targeted protein degradation (TPD) initially centered on the ubiquitin–proteasome system (UPS). Classical PROTACs demonstrated that small molecules could catalytically eliminate intracellular proteins by recruiting E3 ligases. Yet the proteasome has intrinsic constraints:

• It primarily degrades soluble intracellular proteins
• It struggles with large aggregates and organelles
• It cannot directly eliminate extracellular or membrane proteins
• Its activity can be compromised in stressed or diseased cells

These limitations have catalyzed the rise of lysosome- and autophagy-based targeted degradation technologies — modalities that harness the cell’s broader proteostasis and trafficking machinery.

Unlike the proteasome, the lysosome:

• Degrades membrane proteins and extracellular ligands
• Handles protein aggregates and damaged organelles
• Integrates with endocytosis and macroautophagy
• Provides access to previously “undruggable” spatial compartments

This expansion of degradable target space is reshaping therapeutic strategies in oncology, neurodegeneration, immunology, and rare disease.

LYTACs represent a foundational advance in extracellular protein degradation.

LYTACs are bifunctional molecules that bind:

1. An extracellular or membrane-bound target protein
2. A lysosome-shuttling receptor (such as CI-M6PR or ASGPR)

Upon binding, the ternary complex is internalized through endocytosis and trafficked to the lysosome for degradation.

This enables:

• Degradation of secreted cytokines
• Removal of membrane receptors
• Clearance of pathogenic extracellular proteins

Unlike monoclonal antibodies, which typically block function, LYTACs eliminate the target entirely.

• Broad tissue expression
• Established lysosomal trafficking route
• Suitable for systemic applications

• Liver-restricted expression
• Enables hepatocyte-specific degradation
• Valuable for metabolic and liver diseases

Receptor selection determines tissue specificity and therapeutic index.

• Degradation of growth factor receptors
• Removal of immune checkpoint ligands
• Targeting shed extracellular drivers

• Cytokine clearance
• Modulation of inflammatory mediators

• Eliminating profibrotic secreted proteins

LYTACs extend TPD into compartments previously inaccessible to small molecules.

Beyond classical LYTACs, newer modalities refine surface protein degradation strategies.

LYMTACs expand lysosome-directed degradation by targeting lysosomal membrane proteins or alternative internalization routes.

Key differentiators:

• Exploit distinct lysosomal membrane trafficking pathways
• Potentially bypass limitations of CI-M6PR dependency
• Broaden receptor options

LYMTACs increase flexibility in receptor biology and tissue targeting.

PROTABs are antibody-based constructs designed to induce degradation of cell-surface targets.

Mechanistic logic:

• Antibody binds membrane target
• Engages endogenous ubiquitination or internalization machinery
• Drives lysosomal degradation

Unlike classical antibodies that merely block receptor function, PROTABs induce complete target removal.

Advantages over mAbs:

• Sustained target depletion
• Reduced compensatory signaling
• Potential to overcome resistance to receptor blockade

While LYTACs operate via endocytic–lysosomal pathways, other technologies harness macroautophagy, the cell’s bulk degradation system.

Autophagy normally clears:

• Protein aggregates
• Damaged mitochondria
• Intracellular pathogens

Selective autophagy can be induced through engineered proximity strategies.

ATTECs are small molecules that bind both:

• A target protein
• LC3 (a core autophagosome protein)

By tethering the target to LC3, ATTECs promote selective autophagic engulfment and degradation.

• Proteasome-independent
• Effective against aggregate-prone proteins
• Promising in neurodegenerative diseases

• Dependence on autophagic flux
• Potential off-target autophagy activation

AUTACs function differently from ATTECs.

AUTACs mimic S-guanylation signals that induce K63-linked ubiquitination. This modification marks the target for selective autophagic degradation.

• Ubiquitin-dependent autophagy engagement
• Broader compatibility with cellular degradation signals
• Potential organelle targeting applications

AUTACs have been explored for mitochondrial clearance and damaged organelle removal.

AUTOTACs directly recruit the autophagy receptor p62/SQSTM1 to a target.

p62 recognizes ubiquitinated proteins and links them to LC3 on autophagosomes. AUTOTACs bypass ubiquitination complexity by directly engaging p62.

• Simplified recruitment logic
• Potentially more direct autophagy initiation

ULKTACs recruit ULK1, the kinase that initiates autophagosome formation.

Instead of tagging the target for existing autophagy, ULKTACs locally activate autophagy machinery near the target protein.

• Spatially confined autophagy
• Greater control of degradation initiation
• Potential to overcome autophagic flux limitations

Each approach accesses different biological machinery and therapeutic windows.

Many diseases (e.g., neurodegeneration) involve impaired autophagy. Therapeutic success depends on:

• Baseline flux levels
• Lysosomal integrity
• mTOR signaling state

Biomarker development is essential.

Lysosome and autophagy components vary across tissues. Leveraging:

• Receptor-restricted expression (ASGPR)
• Tissue-specific autophagy regulators
• Delivery vectors

can optimize therapeutic index.

Non-selective autophagy induction risks:

• Muscle wasting
• Immune dysregulation
• Metabolic disturbance

Precision recruitment is therefore critical.

Challenges include:

• Large molecular weight
• Cell permeability
• Endosomal escape (for extracellular targeting systems)
• Maintaining ternary complex stability

Structure-guided design and high-content imaging screens are increasingly central.

Autophagy-based degraders are especially promising in:

• Aggregate-prone protein diseases
• Huntington’s disease
• Tauopathies
• Parkinson’s disease

Proteasome systems often struggle with large fibrillar aggregates; autophagy excels in this domain.

In cancer, autophagy plays dual roles:

• Tumor suppression (via proteostasis maintenance)
• Tumor survival under stress

Targeted autophagic degradation can:

• Eliminate oncogenic drivers
• Remove immune evasion proteins
• Target metabolic dependencies

Selective clearance of:

• Cytokines
• Surface immune checkpoints
• Secreted inflammatory mediators

could reshape autoimmune and inflammatory disease treatment.

Diseases caused by:

• Toxic gain-of-function proteins
• Organelle accumulation
• Protein misfolding

may benefit from selective autophagy recruitment strategies.

Biotech companies are rapidly expanding into lysosomal and autophagy platforms, often positioning themselves as:

• “Beyond PROTAC” companies
• Extracellular degradome specialists
• Autophagy-first drug discovery platforms

Key differentiators include:

• Receptor libraries
• Autophagy receptor selectivity
• Tissue-targeting technologies
• Biomarker development capabilities

Pharmaceutical interest is growing due to:

• Access to membrane proteins
• Potential first-in-class opportunities
• Synergy with antibody platforms

As with proteasomal degradation, resistance can emerge through:

• Receptor downregulation
• Lysosomal dysfunction
• Autophagy pathway mutations
• Compensatory signaling pathways

Combination strategies (e.g., mTOR modulation + targeted autophagy) may improve durability.

The next phase of innovation will likely focus on:

• Organelle-specific degradation (mitophagy-targeting chimeras)
• Condensate-associated autophagy
• Tissue-restricted lysosomal receptors
• Small-molecule modulators of autophagy selectivity
• Multi-functional chimeras integrating degradation and signaling control

Integration with:

• Synthetic lethality frameworks
• Spatial pharmacology
• AI-guided ternary complex modeling

will further refine precision.

Autophagy- and lysosome-based targeted degradation technologies represent a decisive expansion of the druggable proteome.

They enable:

• Extracellular protein elimination
• Aggregate clearance
• Organelle removal
• Context-dependent degradation

Where classical PROTACs opened the door to catalytic protein elimination, lysosomal and autophagy modalities unlock the broader spatial architecture of cellular proteostasis.

The field is evolving from simply degrading intracellular proteins to programming cellular disposal systems.

In doing so, drug discovery is transitioning from blocking disease drivers to orchestrating their controlled removal across compartments — inside, outside, and across organelles.

The proteasome was just the beginning.

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Decision makers in biotech face a familiar bottleneck: how to translate a promising biological insight into a tangible lead compound—quickly, cost-effectively, and with minimal downstream risk. Whether your team plans to run an in-house screen or outsource a DNA-encoded library (DEL) campaign to a company such as Vipergen, a clear grasp of antagonists, agonists, allosteric inhibitors, and covalent inhibitors is essential. Each class answers a different strategic question about target engagement, selectivity, dosing cadence, and liability. Below is a concise, evidence-based summary—grounded in peer-reviewed literature—that can inform your next screening and platform choice.

Antagonists bind the orthosteric (native-ligand) site but do not activate the receptor, thereby preventing endogenous signalling. Competitive antagonists vie directly with the agonist; non-competitive and uncompetitive antagonists lower maximal response even at saturating ligand levels. Irreversible antagonists form tight—often covalent—bonds and can block function for the protein’s lifetime.

Competitive antagonists are typically small, drug-like molecules—ideal for large DELs or conventional HTS. Assay windows are wide because antagonism manifests as a rightward shift or flattening of the dose–response curve, metrics that are straightforward to quantify early.

If rapid target shutdown is the therapeutic goal—e.g. blocking cytokine storms or ion-channel hyperactivity—competitive antagonists offer a clear path. Choose a DEL collection rich in heteroaromatic cores and cationic functionalities that mimic natural ligands.

Agonists do more than simply “activate” a receptor; they tune the magnitude—and sometimes the direction—of the response. The matrix below captures the four principal flavours you’ll encounter when planning a screen or evaluating DEL hits.

Key insight: Biased and inverse agonists require signalling-specific assays—standard binding alone will miss them. Build these readouts early to avoid false negatives.

Allosteric inhibitors bind pockets outside the active site, inducing conformational changes that dampen activity. Negative allosteric modulators (NAMs) decrease efficacy; positive allosteric modulators (PAMs) enhance it, and some ligands exhibit ago-allosteric behaviour—weak direct activation plus modulation (Schwarts 2007).

• Superior subtype selectivity—critical when orthosteric sites are highly conserved.
• Saturable modulation—diminishing risk of overdose because allosteric effects plateau.
• Compatibility with endogenous regulation—retaining physiological “tone” rather than silencing the pathway.

Foundational review: Christopoulos outlined the structural logic of GPCR allostery, underscoring how distant pockets dictate finely tuned signalling responses (Christopoulos 2014).

If off-target liability or resistance mutations are primary concerns, allosteric inhibitors shine. Seek DEL panels enriched in larger, three-dimensional chemotypes able to reach cryptic sites.

Irreversible covalent inhibitors form permanent bonds—classically viewed with caution but now resurgent thanks to warhead tuning. Reversible covalent inhibitors use weaker electrophiles or stabilised hemi-aminal linkages, combining long residence time with a defined off-rate.

Modern covalent kinase inhibitors (e.g., osimertinib) illustrate that precision covalency can deliver potency with manageable toxicity. Warhead engineering focuses on tempered electrophiles (acrylamides, cyanoacrylamides) and proximity-driven selectivity.

State-of-the-art overview: Singh et al. traced the renaissance of covalent drugs and laid out warhead design rules that remain central today (Singh 2011). 

Figure 2: Real-World Drug Examples by Inhibitor Class

DELs ley you screen hundreds of millions of compounds against your target in a single tube, capturing binders via affinity selection or Vipergen’s DEL screening in cells and decoding them by next-generation sequencing. Recent reviews documents DEL-driven discovery of nanomolar ligands across kinases, GPCRs, and protein-protein interaction inhibitors.

Vipergen’s DEL screening platform delivers:

• High Fidelity libraries – Our libraries are synthesized utilizing the Yoctoreactor which gives a complete match between DNA barcode and molecule without any truncated products.

• Highly diverse libraries, which are designed to be sp3-rich, have high 3D diversity and be rule-of-5 compliant. 

• Screening inside living cells – Our proprietary technology allows us to screen directly for e.g. molecular glues, PPI inhibitors and integrated membrane proteins. See the full list of services here.

• Rapid hit-resynthesis – we can perform off-DNA resynthesis for you, for direct hit-validation.

For decision makers balancing budget, speed, and risk, a DEL campaign de-risk early discovery and delivers structure-activity clues up-front – especially when inhibitor class is still fluid. 

• Class drives strategy: Antagonist, agonist, allosteric inhibitor, or covalent inhibitor each solves a different pharmacological problem. 

• Match assay to mechanism: Screening readouts and kinetic endpoints must align with desired mode of action.

• Leverage DEL flexibility: Modern DEL chemistry can explore every inhibitor class in parallel, collapsing timelines and cost. 

• Invest in structural insight early: Orthosteric versus allosteric binding will dictate downstream medicinal chemistry. 
• Partner for speed: External platforms with validated on-DNA chemistries accelerate the path to a qualified lead.

• Christopoulos, A., Advances in G Protein-Coupled Receptor Allostery: From Function to Structure, Mol. Pharmacol., 2014, 86 (5), 463-478. doi.org/10.1124/mol.114.094342 
• Schwartz, T. W. et. al., Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?, Trends Pharmacol. Sci., 2007, 28 (8), 366-373. doi.org/10.1016/j.tips.2007.06.008
• Singh, J. et. al., The resurgence of covalent drugs, Nat. Rev. Drug Discov., 2011, 10, 307-311. doi.org/10.1038/nrd3410 

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