Design and SAR Strategy for Selective Cyclin-Dependent Kinase 2 (CDK2) PROTAC Degraders

Keywords

CDK2 - PROTAC - selective degraders - antitumor activity - CCNE1

Significance

CDK2 has gained significant interest as a strategy to overcome resistance to CDK4 /6 inhibitors which have served as the standard of care for HR + /HER2– advanced or metastatic breast cancer for nearly a decade, typically in combination with endocrine therapy. This article reports the discovery of a selective CDK2 PROTAC degrader derived from Pfizer’s CDK2 /4 /6 inhibitor. The authors achieved CDK2 selectivity over other CDKs by identifying selective inhibitors and further optimized selectivity, ADME properties, and efficacy through careful PROTAC linker design and subtle modifications at both termini of the molecules. Given the therapeutic challenge of acquired resistance to CDK4 /6 inhibitors, the development of selective CDK2 PROTAC degraders represents a promising strategy to address this unmet need.

Comment

The selective CDK2 inhibitor was discovered through extensive SAR of the lead 1 derived from Pfizer’s CDK2 /4 /6 inhibitor by dialing out CDK4 /6 activities through CDK2 specific interactions. The resulting inhibitor 2 was utilized to design selective PROTAC degraders in association with a CRBN binder. Subsequent SAR exploration encountered a series of challenges, including: (1) Low degradation potency and selectivity over CDK1 of 3 were improved by shortening the linkers; (2) CYP3A4 TDI liability of 4 was mitigated by preventing quinone methide reactive metabolite formation through replacing ‘Me’ with ‘F’; (3) Low human intrinsic clearance was addressed by reducing basicity of piperidine linker. Overall, this article provides a clear account of the strategic rationale and SAR efforts that culminated in the discovery of candidate 5.

Publication History

Article published online:
30 October 2025