Developing first-in-class induced proximity therapeutics

Proxygen is building a pipeline of first-in-class induced proximity therapeutics designed to control disease-driving proteins that have historically remained difficult to address with conventional drug modalities.

By systematically identifying productive interactions between targets and cellular effector proteins, Proxygen aims to unlock new therapeutic mechanisms and expand the reach of small-molecule drug discovery.

Our most advanced programs, p300 and CDK12, illustrate how molecular glue degraders can reprogram transcriptional dependencies that sustain tumor growth and resistance across multiple cancer types.

Discovery Hit-to-Lead Lead OP Clinical

  • P300

    Glue degrader
    Program highlights
    • First-in-class oral glue degrader targeting the transcriptional co-activator p300
    • Sub-nanomolar potency with differentiated covalent glue pharmacology
    • Catalytic degradation enabling durable activity and PK/PD decoupling
    • Targeting transcription-driven cancers including prostate, lung, and bladder cancer
    Target biology

    p300 is a histone acetyltransferase and epigenetic co-activator that regulates enhancer activation and chromatin accessibility. Through this role, p300 sustains oncogenic transcriptional programs driven by key cancer drivers including the androgen receptor (AR), MYC, and estrogen receptor (ER).

    Many tumors become dependent on p300 to maintain these transcriptional networks, making it an attractive therapeutic target across multiple cancers. Tumors harboring loss-of-function mutations in the paralog CBP develop a synthetic lethal dependency on p300, creating biomarker-defined patient populations where p300 targeting may be particularly effective.

    Therapeutic opportunity

    Despite strong biological validation, p300 has historically been difficult to target therapeutically. As a central transcriptional co-activator, p300 regulates gene expression programs that drive tumor growth and survival across multiple cancer types, making it an attractive target for oncology drug discovery.

    However, developing effective therapies against p300 has proven challenging. p300 and its closely related paralog CBP share highly conserved functional domains, making selective inhibition difficult with traditional small-molecule approaches. Dual inhibition of both proteins has been associated with dose-limiting toxicities due to their essential role in megakaryocyte differentiation.

    As a result, classical inhibitor strategies have struggled to achieve a sufficient therapeutic window. Targeted protein degradation introduces a fundamentally different pharmacological approach – one that may enable durable suppression of oncogenic transcriptional programs while decoupling biological activity from systemic drug exposure.

    Proxygen's approach

    Our molecules induce targeted degradation of p300, enabling modulation of transcriptional programs that drive tumor growth.

    A central feature of this program is the unique pharmacology of covalent glue degraders. Through covalent programming of the recruited E3 ligase, the degrader mechanism acts catalytically, enabling durable target degradation even after compound exposure declines. This creates a decoupling of pharmacokinetics (PK) and pharmacodynamics (PD) and may allow sustained biological effects at lower systemic exposure.

    p300 degradation suppresses oncogenic transcriptional programs and has demonstrated robust anti-tumor activity in preclinical models.

    Together, the combination of high potency, catalytic degradation, and durable pharmacology creates the potential for a meaningful therapeutic window.

  • CDK12

    Glue degrader
    Program highlights
    • First-in-class glue degrader inactivating CDK12 via Cyclin K degradation
    • High selectivity across the CDK family through a differentiated degradation mechanism
    • Brain-penetrant molecules designed to address HER2-driven CNS metastases
    • Targeting transcriptional dependencies in HER2-driven cancers beyond HER2-directed therapies
    Target biology

    CDK12 is a transcriptional kinase that regulates gene expression programs involved in DNA damage repair, transcriptional elongation, and oncogenic signaling.

    In HER2-positive cancers, CDK12 is frequently co-amplified with HER2 due to their proximal location on chromosome 17. This genetic linkage contributes to tumor growth and may support resistance to HER2-directed therapies.

    As a result, many HER2-driven tumors become dependent on CDK12 activity to maintain key transcriptional programs, creating a therapeutic opportunity to target this vulnerability independently of HER2 itself.

    Therapeutic opportunity

    Despite strong biological rationale, CDK12 has proven challenging to drug therapeutically. Members of the cyclin-dependent kinase family share highly conserved catalytic pockets, making it difficult to achieve sufficient selectivity with traditional kinase inhibitors.

    At the same time, HER2-positive cancers frequently develop resistance to HER2-directed therapies and often progress to brain metastases, where many currently available treatments show limited activity.

    These limitations create a need for therapeutic strategies that address the underlying transcriptional and genomic dependencies that sustain HER2-driven tumors, including disease that has spread to the central nervous system.

    Proxygen's approach

    Proxygen is developing glue degraders that inactivate CDK12 through targeted degradation of its binding partner Cyclin K, a critical component of the CDK12 transcriptional complex.

    By eliminating Cyclin K, this approach disrupts CDK12-dependent transcriptional programs required for tumor cell survival while maintaining high selectivity across the broader CDK family.

    Importantly, Proxygen’s molecules are designed to penetrate the blood-brain barrier, creating the potential to address HER2-driven cancers that frequently metastasize to the central nervous system.

    Together, the combination of a differentiated mechanism of action, high selectivity, and brain-penetrant pharmacology positions this program to target transcriptional dependencies in HER2-driven cancers beyond the reach of conventional HER2-directed therapies.

  • #3

    Glue degrader

  • #4

    Glue degrader

  • #5

    Beyond degradation

Partnered programs

  • Undisclosed

Induced proximity beyond degradation

Glue degraders have demonstrated the power of induced proximity in drug discovery. By bringing a target protein into proximity with an E3 ligase, small molecules can selectively eliminate disease-driving proteins and unlock targets that were previously considered undruggable. Through its discovery platform designed to identify productive target–ligase pairings, Proxygen has built deep expertise in this emerging therapeutic modality.

However, induced proximity extends far beyond protein degradation.

Bringing proteins into controlled functional contact can modulate biology in many ways. Depending on the proteins involved, induced proximity can alter protein activity, stability, localization, or interactions within regulatory complexes. Rather than simply eliminating a protein, these

mechanisms allow biological processes to be reprogrammed with precision, creating opportunities to address targets where simple loss of function may be insufficient.

Building on years of experience in molecular glue degrader discovery, Proxygen is expanding its platform to explore induced proximity mechanisms beyond ligase recruitment. By applying its expertise in identifying productive protein pairings to additional effector proteins, the company aims to unlock new therapeutic strategies across a broad range of disease-relevant pathways.

Together, these efforts position Proxygen to help define the next generation of induced proximity therapeutics, expanding the reach of this modality beyond degradation toward a broader toolkit for precisely controlling cellular biology.

“The next revolution in medicine won’t come from doing more of the same. Induced proximity unlocks what traditional pharmacology never could. We are the team bold enough to chase it.”

Bernd Boidol