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Selective CDK2 Degradation via Noncanonical Recruitment

Yuanyuan Pei1,2, Weiye Lin3,2, Xinzhu Li2,4

  • 1School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.

Journal of Medicinal Chemistry
|June 23, 2026
PubMed

Insights

New molecular glues, B10 and B12, selectively degrade Cyclin-dependent kinase 2 (CDK2) by a unique mechanism. This discovery offers a promising strategy for targeting CDK2-driven cancers, with B12 showing strong in vivo efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 2 (CDK2) is a key therapeutic target in cancers resistant to CDK4/6 inhibitors or with CCNE1 amplification.
  • Selective CDK2 inhibition is challenging due to high structural homology among CDK family members.

Purpose of the Study:

  • To identify and characterize novel molecular degraders that selectively target CDK2.
  • To elucidate the structural and mechanistic basis for selective CDK2 degradation.

Main Methods:

  • Identification of cereblon (CRBN)-based molecular glue degraders (B10 and B12).
  • Determination of ternary complex structures between CRBN, CDK2, and the degraders.
  • Assessment of mechanistic effects on cell cycle progression and in vivo pharmacokinetics and target engagement.

Main Results:

  • B10 and B12 were identified as selective CDK2 degraders.
  • A noncanonical recruitment mode involving CDK2 Glu57 was revealed, stabilized by an extended CRBN-CDK2 interface.
  • Degraders induced G1/S-phase arrest by inhibiting retinoblastoma (Rb) phosphorylation and suppressed CDK2-dependent proliferation.
  • B12 demonstrated favorable pharmacokinetics, oral bioavailability, and in vivo intratumoral CDK2 degradation.

Conclusions:

  • The study provides a structural basis for designing selective kinase degraders.
  • B12 is established as a chemically tractable probe for targeting CDK2-driven malignancies.

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