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

Related Experiment Video

Updated: Sep 10, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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Philip N Collier1, Xiaozhang Zheng1, Melissa Ford1

  • 1Kymera Therapeutics Inc., 500 North Beacon Street, Watertown, Massachusetts 02472, United States.

Journal of Medicinal Chemistry
|August 20, 2025
PubMed

Insights

Researchers developed novel, selective degraders of cyclin-dependent kinase 2 (CDK2) to target cancer. Degrader 37 showed promising antitumor activity and specificity in preclinical models, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 2 (CDK2) is crucial for cell cycle regulation and a target for cancer therapy.
  • CDK2 inhibition may overcome resistance to CDK4/6 inhibitors.
  • Developing selective CDK2 inhibitors is challenging due to off-target effects.

Purpose of the Study:

  • To discover orally bioavailable and selective degraders of CDK2.
  • To identify compounds with improved specificity for cancer cells with cyclin E1 (CCNE1) amplification.

Main Methods:

  • Structure-guided drug design.
  • Synthesis and evaluation of novel CDK2 degraders.
  • In vitro phenotypic selectivity assays.
  • In vivo studies in mouse xenograft models.

Main Results:

  • Discovery of orally bioavailable and selective CDK2 degraders.
  • Degrader 37 exhibited enhanced phenotypic selectivity for CCNE1-amplified cancer cells.
  • Degrader 37 demonstrated significant antitumor activity in vivo.
  • Observed sustained degradation of CDK2 and inhibition of Rb phosphorylation.

Conclusions:

  • Structure-guided design yielded potent and selective CDK2 degraders.
  • Degrader 37 represents a promising therapeutic candidate for CCNE1-amplified cancers.
  • This approach offers a strategy to overcome resistance to existing cancer therapies.

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