2. Academic Validation
  3. Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2

Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2

  • J Med Chem. 2025 Sep 11;68(17):18407-18422. doi: 10.1021/acs.jmedchem.5c01160.
Philip N Collier 1,  Xiaozhang Zheng 1,  Melissa Ford 1,  Matthew Weiss 1,  Dapeng Chen 1,  Kunhua Li 1,  Joseph D Growney 1,  Annan Yang 1,  Murugappan Sathappa 1,  Susanne B Breitkopf 1,  Brad Enerson 1,  Tong Liang 1,  Atanu Paul 1,  Rupa Sawant 1,  Lijing Su 1,  Robert J Aversa 1,  Charles Howarth 1,  Kirti Sharma 1,  Juliet Williams 1,  Nicholas P Kwiatkowski 1
Affiliations

Affiliation

  • 1 Kymera Therapeutics Inc., 500 North Beacon Street, Watertown, Massachusetts 02472, United States.
PMID: 40833690 DOI: 10.1021/acs.jmedchem.5c01160
Abstract

Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of Cancer, largely because of its potential to overcome the resistance associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors have historically proven challenging due to undesirable safety profiles associated with inhibiting off-target CDK isoforms. Herein, we describe the structure-guided discovery of a series of orally bioavailable and selective degraders of CDK2. Degrader 37 demonstrated improved phenotypic selectivity compared to a clinical CDK2 Inhibitor, with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified Cancer cells vs nonamplified cohort. The antitumor activity of 37 in mice bearing CCNE1-amplified HCC1569 tumors correlated with sustained >90% degradation of CDK2 and sustained 90% inhibition of Rb phosphorylation.

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