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TitleSelective CDK2 Degradation via Noncanonical Recruitment.
Journal, issue, pagesJ. Med. Chem., Year 2026
Publish dateFeb 16, 2026 (structure data deposition date)
AuthorsYuanyuan Pei / Weiye Lin / Xinzhu Li / Yuhang Meng / Yuling Yin / Benxun Pan / Lixin Zhou / Linhui Cao / Yong Cang / Yi Jiang / Wenchao Lu / Zhanchao Meng /
PubMed AbstractCyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with amplification. However, selective inhibition of CDK2 remains challenging ...Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with amplification. However, selective inhibition of CDK2 remains challenging owing to the high structural homology among CDKs. In this study, we identify and 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/β-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. further exhibits improved pharmacokinetics, measurable oral bioavailability, and 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.
External linksJ. Med. Chem. / PubMed:42334090
MethodsEM (single particle)
Resolution2.85 Å
Structure data

PDB-23sr:
Cryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11
Method: ELECTRON MICROSCOPY / Resolution: 2.85 Å

Chemicals

PDB-1e59:
E.coli cofactor-dependent phosphoglycerate mutase complexed with vanadate

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsCELL CYCLE / Cyclin-Dependent Kinase 2 / Cereblon / Molecular glue / Complex

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