Abstract A026: Discovery of potent and selective CDK2 molecule glue degraders for the treatment of HR+/HER2- breast cancer, and CCNE1 amplified tumors

Abstract Introduction: The Cyclin-Dependent Kinase 2 (CDK2) is a key oncology target and promotes cell cycle progression by binding to its cyclin binding partners, especially, Cyclin E (CCNE1). The activated CCNE1/CDK2 complex phosphorylates RB and promotes cellular proliferation. CCNE1 amplification/overexpression drives aberrant cell cycle progression, and is associated with poor prognosis in multiple cancers, including ovarian and breast cancers. Activation of CDK2 by amplified CCNE1 is a key resistance mechanism in CDK4/6 inhibitor breast cancer therapy. Current CDK2 inhibitors are limited by their diminished selectivity at efficacious exposures due to high similarity in the ATP-binding sites of other CDKs. Molecular glue degraders of CDK2 offer an attractive alternative strategy to achieve selective downregulation of CDK2 providing potential for improved clinical benefit. Result: Plexium’s integrated monovalent degrader platform resulted in the identification of novel, potent and selective CRBN-based CDK2 molecular glue (MG) degraders. Cryo-EM structures of the CRBN:MG:CDK2 ternary complex revealed a unique degradation complex that led to the design of multiple novel MG chemical series. Degradation potency was profiled using a HiBiT CDK2 cell line demonstrating dose dependent and proteasome mediated degradation. Dependency on CRBN was confirmed using a knock-out cell line; binding potency to CRBN also correlated with CDK2 degradation DC50. Potency and stability of CRBN:MG:CDK2 ternary complex formation corresponded with CDK2 degradation in both DC50 and Dmax. Global proteomics demonstrated that these molecules were highly selective CDK2 degraders, without modulation of other CDKs or known CRBN neo-substrates and resulted in downregulation of E2F target proteins. Selective CDK2 degraders demonstrated potent inhibition of RB phosphorylation, cell cycle arrest and antiproliferative activity in CCNE1 amplified vs non-amplified cancer cell lines. This is in contrast with ATP-competitive clinical stage small molecule CDK2 inhibitors where selectivity is eroded at high concentrations due to potential inhibition of CDK off-targets. No inhibitory activity was observed for the CDK2 degraders across a broad kinase panel, confirming the cellular activity was a result of CDK2 protein loss. Oral administration of CDK2 degraders demonstrate in vitro-in vivo PK/PD correlation and anti-tumor activity in CCNE1 amplified mouse xenograft models. Conclusion: We have discovered novel molecular glues that selectively degrade CDK2 resulting in preferential anti-proliferative activity in CCNE1 amplified cells with superior activity relative to ATP-competitive small molecule CDK2 inhibitors. CDK2 degraders result in potent degradation and anti-tumor activity in vivo. This supports the potential for CDK2 molecular glue degraders to treat CDK4/6 inhibitor-naïve and -resistant HR+/HER2- breast cancer, and CCNE1 amplified patient populations. Citation Format: Nasrin Rastgoo, Leenus Martin, Jean-Francois Brazeau, Quinn Spalding, Gabrielle Blanco, Kyohei Hayashi, Susan Song, Jianguo Ma, Shu You, Alex Campos, Julia Toth, Jay Chung, Farhana Barmare, Hongfeng Gao, Meg McCarrick, Kevin Freeman-Cook, Peggy A. Thompson. Discovery of potent and selective CDK2 molecule glue degraders for the treatment of HR+/HER2- breast cancer, and CCNE1 amplified tumors [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 A026.