Abstract B052: PXG-CycK, a highly selective molecular glue degrader of Cyclin K with potent anti-tumor activity in HER2-amplified cancers

Abstract Background: Cyclin K is an essential cofactor for CDK12 and CDK13, kinases that govern transcriptional and processing of genes critical for DNA repair, cell cycle progression and oncogenic signaling. Amplification of CDK12 frequently co-occurs with HER2 due to their close genomic proximity, resulting in more aggressive disease and increased dependency on CDK12 activity. However, traditional ATP-competitive CDK inhibitors have shown limited clinical utility unless high selectivity for individual family members is achieved, due to the toxicities associated with broad CDK inhibition. The CDK12/Cyclin K axis was thus left unexploited due to lack of agents with sufficient selectivity. Results: PXG-CycK is a potent and orally bioavailable small molecule degrader of Cyclin K, discovered via Proxygen’s ligase-agnostic screening platform. Combining many advantages of molecular glue degraders, PXG-CycK degrades Cyclin K with exquisite selectivity across the CDK family, avoiding collateral targeting of other CDK:Cyclin complexes. Thanks to its catalytic mechanism of action, it further exhibits an unprecedented clean kinase inhibition profile, as Cyclin K degradation happens at concentrations 2000-fold lower than kinase inhibition of the closely related CDK7 and CDK9. This selectivity is reflected in a differentiated transcriptional response compared to other CDK-targeting agents, resulting in superior tolerability and lack of hematological toxicity in vivo. In HER2-amplified breast cancer models, PXG-CycK elicited tumor regression as single agent across multiple xenograft models with no adverse impact on body weight, hematology or clinical chemistry. Furthermore, PXG-CycK synergizes in vitro with standard-of-care anti-HER2 agents, highlighting its potential for combination strategies in HER2-driven malignancies. Conclusion: PXG-CycK represents a Cyclin K degrader with best-in-class profile with a novel mechanism of action, exceptional CDK selectivity, and a compelling preclinical safety profile. Its robust activity in HER2-driven models positions it as a promising candidate for clinical development in breast and other solid tumors. These attributes position PXG-CycK as a promising therapeutic candidate, now advancing into clinical development, and offer a compelling new class of drugs in HER2-positive cancers, other CDK12/Cyclin K-dependent malignancies and Homologous Repair-deficient tumors, such as TNBC and ovarian cancer. Citation Format: Vanessa Nancy-Portebois, Douglas Thomson, Tobias Schubert, Lisa Landskron, Michael Caldera, Ioanna Styliara, Dominik Gassner, Francis Forster, Styliani Karagiorgou, Tamara Halter, Kalina Bozhkova, Kristyna Judas, Mirella Nader-Bellis, Georg Winter, Adam Davenport, Matthias Brand. PXG-CycK, a highly selective molecular glue degrader of Cyclin K with potent anti-tumor activity in HER2-amplified cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B052.