Abstact

Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with CCNE1 amplification. However, selective inhibition of CDK2 remains challenging owing to the high structural homology among CDKs. In this study, we identify B10 and B12 as cereblon (CRBN)-based molecular glue degraders that selectively degrade CDK2. Ternary complex structures reveal a noncanonical recruitment mode centered on CDK2 Glu57, which bypasses the canonical G-loop/beta-hairpin and kinase glycine-rich loop interactions and is stabilized by an extended CRBN-CDK2 interface. Mechanistically, these degraders inhibit retinoblastoma (Rb) phosphorylation and induce G1/S-phase arrest, suppressing CDK2-dependent cell proliferation. B12 further exhibits improved pharmacokinetics, measurable oral bioavailability, and in vivo target engagement, achieving intratumoral CDK2 degradation following intraperitoneal administration. Collectively, this study provides a structural blueprint for designing selective kinase degraders and establishes B12 as a chemically tractable probe for targeting CDK2-driven malignancies.