Abstract 4600: Discovery of PLX-66140, a first-in-class, potent and selective CDK2 molecular glue degrader for CCNE1-amplified tumors

Abstract Introduction: Dysregulation of the cell cycle is a hallmark of many cancers. The Cyclin-Dependent Kinases (CDKs) with their cyclin binding partners are associated with cell cycle progression and transcriptional regulation. Targeting CDK2 is a key therapeutic strategy in oncology, especially in Cyclin E1 (CCNE1) amplified/overexpressed and ER+ breast cancers. 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, breast and uterine cancers. 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 our development candidate, PLX-66140, a novel, potent and selective cereblon (CRBN) based CDK2 molecular glue degrader for the treatment of CCNE1 amplified cancers. Plexium’s ultra-high throughput screening platform and medicinal chemistry optimization efforts identified our lead molecular glue degrader that induces CRBN-CDK2 ternary complex formation and demonstrates proteasomal dependent, CRBN-mediated degradation of CDK2 in cell-based assays. Global proteomics confirms that PLX-66140 degrades CDK2 selectively without modulating known cereblon neosubstrates and exhibits dose dependent modulation of E2F target genes. Potent, deep and selective degradation of CDK2 with PLX-66140 treatment, results in robust inhibition of RB phosphorylation, cell cycle arrest and antiproliferative activity in a panel of CCNE1 amplified cancer cell lines. In contrast to ATP-competitive small molecule inhibitors, PLX-66140 demonstrates selective inhibition of cell cycle arrest and proliferation in CCNE1 amplified cells, and minimal activity in non-CCNE1 amplified cells, highlighting the selectivity and potential superior safety profile over inhibitors. Oral administration of PLX-66140 in tumor bearing mice demonstrates robust target degradation and enhanced anti-tumor activity over ATP-competitive inhibitors in multiple CCNE1 amplified xenograft models at well tolerated doses. Conclusion: Our development candidate, PLX-66140 provides compelling preclinical evidence and scientific rationale for clinical development in CDK4/6 inhibitor-naïve and -resistant HR+/HER2- breast cancer along with CCNE1 amplified solid tumors. Citation Format: Leenus Martin,Jean-Francois Brazeau,Nasrin Rastgoo,Quinn Spalding,Gabrielle Blanco,Kyohei Hayashi,Susan Song,Jianguo Ma,Shu You,Campos Alex,Jay Chung,Farhana Barmare,Kevin Freeman-Cook,Peggy A. Thompson. Discovery of PLX-66140, a first-in-class, potent and selective CDK2 molecular glue degrader for CCNE1-amplified tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4600.