Abstract 3309: Discovery of potent and selective bivalent CDK2 degraders that demonstrate activity in CCNE1amp driven tumors
Authors: Gerson-Gurwitz Adina , Yang Pengyu , Fish Sarah , Blanco Gabrielle , Gao Hongfeng , Hayashi Kyohei , Hocker Mike , Jamborcic Aleks , Richters Andre , Spalding Mary E. , Toth Julia , Tran Duc , Yang Linette , You Shu , Burritt Andrew , Campos Alex , Parker Gregory , Freeman-Cook Kevin , Thompson Peggy A. , Bailey Simon 
Published: March 2024

Introduction: The Cyclin-Dependent Kinases (CDKs) with their cyclin binding partners, are associated with cell cycle progression and transcriptional regulation. Targeting CDKs is a key oncology therapeutic strategy with CDK4/6 inhibitors demonstrating significant clinical benefit in HR+/HER2− metastatic breast cancer, the most prevalent subtype. However, 30% of patients develop acquired resistance in the clinic with cyclin E1 (CCNE1) amplification/overexpression and CDK2 activation implicated as a major resistance mechanism to CDK4/6i breast cancer therapy. Additionally, CCNE1/CDK2 activation has also been associated with poor prognosis in ovarian and endometrial cancers. Selective targeting of CDK2 using small molecule inhibitor-based approaches have recently advanced into the clinic. Targeted protein degradation of CDK2 provides an alternative strategy that has the potential to eliminate the activity of the CCNE1/CDK2 complex, as well as CDK2 complexed with other cyclins, including cyclin A, and provide improved clinical benefit.

Results: Discovery efforts at Plexium have identified CDK2 bivalent degraders that consist of a CDK2-binding moiety, a linker and a high affinity cereblon-binding ligand. Cereblon binding potency was found to correlate with potent and deep degradation of CDK2. Degradation was blocked in the presence of a proteasome inhibitor as well as in a cereblon knock-out cell line, confirming that CDK2 degradation is mediated by the ubiquitin proteasome system and through engaging cereblon. Proteome-wide analysis demonstrated that CDK2 was selectively depleted without significantly modulating other CDKs or known cereblon neo-substrates. Selective degradation was achieved despite lack of selectivity for binding/inhibition of other CDKs and was confirmed to be dependent on the formation of a CRBN-CDK2 ternary complex. Dose dependent CDK2 degradation resulted in dose dependent inhibition of Rb phosphorylation, cell cycle arrest, senescence-associated phenotypes and antiproliferative activity in CCNE1 amplified cancer cell lines. The in vitro data was used to evaluate the PK/PD drug exposure-response relationship in vivo and deep CDK2 degradation was demonstrated both in vitro and in vivo.

Conclusions: These data provide validation for CDK2 degradation as a therapeutic approach. Potent and selective CDK2 bivalent degraders were exploited as tools for studying the sensitivity of CCNE1 amplified tumor models to CDK2 degradation and dependence on E3 ligase. This proof-of concept study supports Plexium’s current approach of discovering novel CDK2 molecular glue degraders for the treatment of CDK4/6 inhibitor-naïve and -resistant HR+/HER2− breast cancer, and CCNE1 amplified ovarian and endometrial cancers.

Citation Format: Adina Gerson-Gurwitz, Pengyu Yang, Sarah Fish, Gabrielle Blanco, Hongfeng Gao, Kyohei Hayashi, Mike Hocker, Aleks Jamborcic, Andre Richters, Mary E. Spalding, Julia Toth, Duc Tran, Linette Yang, Shu You, Andrew Burritt, Alex Campos, Gregory Parker, Kevin Freeman-Cook, Peggy A. Thompson, Simon Bailey. Discovery of potent and selective bivalent CDK2 degraders that demonstrate activity in CCNE1amp driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3309.