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
  • 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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