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Updated: Jun 23, 2026

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

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Utilizing Molecular Dynamics and Mechanistic Pharmacokinetic Studies in the Design of Selective CDK2 Inhibitors

Vishal A Verma1, Jessica M Grandner1, Brendan T Parr1

  • 1Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

Journal of Medicinal Chemistry
|June 22, 2026
PubMed

Insights

Researchers developed a new drug, compound 19, to overcome resistance in HR-positive breast cancer by selectively inhibiting CDK2. This targeted therapy showed significant tumor growth inhibition in preclinical models.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Cyclin-dependent kinase (CDK) 4/6 inhibitors are standard care for HR-positive breast cancer.
  • Acquired resistance to CDK4/6 inhibitors is a significant clinical challenge.
  • Emerging evidence implicates CDK2 in resistance mechanisms.

Purpose of the Study:

  • To develop novel therapeutics targeting CDK2 to overcome resistance to CDK4/6 inhibitors.
  • To achieve selectivity for CDK2 over the essential CDK1.
  • To optimize pharmacokinetic properties for in vivo efficacy.

Main Methods:

  • Medicinal chemistry campaign guided by molecular dynamics simulations.
  • Structure-based drug design focusing on active site interactions.
  • Pharmacokinetic profiling in rats and in vivo efficacy studies in a xenograft model.

Main Results:

  • Compound 19 demonstrated potent inhibition of CDK2 with selectivity over CDK1 and CDK4.
  • Molecular dynamics identified key interactions for achieving CDK1 selectivity.
  • Compound 19 exhibited favorable pharmacokinetics, including overcoming efflux-driven clearance.
  • Nearly 80% tumor growth inhibition was observed in a CDK2-driven xenograft model.

Conclusions:

  • Selective CDK2 inhibition represents a promising strategy to overcome resistance to CDK4/6 inhibitors in breast cancer.
  • Compound 19 is a potent and selective CDK2 inhibitor with demonstrated in vivo efficacy.
  • Understanding and modulating drug clearance mechanisms are crucial for optimizing therapeutic outcomes.

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