PhoRCs and PhICs: The Next Wave of Induced-Proximity Drugs
Beyond degradation: a new class of induced-proximity drugs
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.
What are PhoRCs and PhICs?
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.”
How PhoRCs and PhICs work
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].
PhoRCs and PhICs vs. PROTACs and molecular glues
| Modality | Effector hijacked | Effect on target | Reversible / catalytic? | Representative example |
|---|---|---|---|---|
| PROTAC |
E3 ubiquitin ligase (e.g., CRBN, VHL) |
Ubiquitination → proteasomal degradation |
Catalytic turnover, but the outcome is irreversible once degradation completes | VHL- and CRBN-recruiting degraders in clinical development [1] |
| Molecular glue | E3 ubiquitin ligase, via a single small molecule with no linker |
Ubiquitination → proteasomal degradation |
Catalytic turnover, irreversible outcome | Immunomodulatory imide drugs (IMiDs) [1] |
| PhoRC / PhosTAC |
Protein phosphatase (e.g., PP1, PP5) |
Site-specific dephosphorylation | Catalytic and reversible – the target protein remains intact | PP5-recruiting ASK1 dephosphorylator [7] |
| PhIC | Kinase (e.g., AMPK, PKC) | Site-specific (neo-)phosphorylation | Catalytic and reversible | AMPK/PKC-recruiting BRD4 phosphorylator [3] |
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].
Why target phosphorylation instead of degradation?
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.
Industry momentum: Photys Therapeutics and beyond
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 discovery bottleneck
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.
How DNA-encoded library screening accelerates PhoRC and PhIC discovery
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.
Frequently asked questions
A PhoRC recruits a phosphatase to remove a phosphate group from a target protein (dephosphorylation); a PhIC recruits a kinase to add one (phosphorylation). They are mechanistic mirror images of the same induced-proximity idea [3, 8].
Functionally, yes. “PhosTAC” (phosphorylation-targeting chimera) is an earlier, independently coined term for what much of the field now also calls a PhoRC: a bifunctional molecule that recruits a phosphatase to a target protein [4, 5].
No. Both are heterobifunctional, induced-proximity molecules, but a PROTAC recruits an E3 ubiquitin ligase to destroy its target, while a PhIC recruits a kinase to phosphorylate — not destroy — its target [1, 3].
The next frontier after degraders
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.
References
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[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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