Abstract 6375: Discovery and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors

Abstract Introduction: The Cyclin-Dependent Kinases (CDKs) with their cyclin binding partners are associated with cell cycle progression and transcriptional regulation. Dysregulation of the cell cycle is a hallmark of cancer and targeting CDKs is a key oncology therapeutic strategy. Cyclin E1 (CCNE1) amplification/overexpression and activation of its canonical binding partner CDK2 is a major resistance mechanism in CDK4/6i breast cancer therapy. In addition, elevated CCNE1 expression and complexation with CDK2 promotes aberrant cell cycling which is associated with poor prognosis in ovarian and breast cancers. Currently, targeting CDK2 using small molecule active site inhibitor-based approaches have advanced into the clinic. However, maintaining selective CDK2 inhibition at efficacious exposures is challenging due to the high sequence homology across other CDKs. Molecular glue degraders have the potential to selectively target CDK2 and provide improved clinical benefit while minimizing off-target toxicities. Results: Here we report the discovery of novel, potent and selective CRBN-based CDK2 molecular glue degraders for the treatment of CCNE1 amplified cancers. Our lead CDK2 molecular glue degraders exhibit potent and proteasomal dependent degradation of CDK2 in HiBiT reporter assays. CRBN-dependent degradation of CDK2 is confirmed by CRBN knockout, and formation of a CRBN-CDK2 ternary complex in cells. Proteome-wide analysis shows selective degradation of CDK2 and minimal effects on other known cereblon neosubstrates. Overall, CDK2 degraders exhibit superior selectivity relative to ATP-competitive small molecule inhibitors. Lead molecular glues demonstrate potent and selective degradation of CDK2, resulting in inhibition of RB phosphorylation, cell cycle arrest and antiproliferative activity in CCNE1 amplified cancer cell lines. Oral administration of CDK2 degraders in vivo demonstrate in vitro-in vivo PK/PD correlation and robust anti-tumor activity in CCNE1 amplified mouse xenograft models. Conclusion: Our potent and selective CDK2 molecular glue degraders provide preclinical evidence and scientific rationale for the treatment of CDK4/6 inhibitor-naïve and -resistant HR+/HER2- breast cancer, and CCNE1 amplified ovarian, gastroesophageal, and uterine cancers. Citation Format: Leenus Martin, Nasrin Rastgoo, 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 and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6375.