Related Experiment Video

Updated: Jul 11, 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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Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent

David B Freeman1,2, Tamara D Hopkins1,2, Peter J Mikochik1,2

  • 1Kronos Bio, Inc., 301 Binney Street, 2nd Floor East, Cambridge, Massachusetts 02142, United States.

Journal of Medicinal Chemistry
|November 15, 2023
PubMed

Insights

Researchers optimized a molecule to create a potent and selective CDK9 inhibitor, KB-0742. This drug shows promise for treating solid tumors and is now in clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Transcriptional deregulation, driven by oncogenes like MYC, is common in cancers.
  • Targeting transcriptional cofactors and cyclin-dependent kinase 9 (CDK9) is a therapeutic strategy.

Purpose of the Study:

  • To structurally optimize a CDK9 inhibitor for improved potency, selectivity, and pharmacokinetic properties.
  • To discover a drug candidate for treating cancers with deregulated transcription.

Main Methods:

  • Structure-based drug design and medicinal chemistry.
  • In vitro assays for potency and selectivity.
  • In vivo studies in mouse xenograft models.
  • Pharmacokinetic profiling.

Main Results:

  • Discovery of compound 28 (KB-0742), a potent and selective oral CDK9 inhibitor.
  • Demonstrated in vivo antitumor activity in preclinical models.
  • Projected favorable human pharmacokinetic profile for oral administration.

Conclusions:

  • KB-0742 is a promising drug candidate for treating solid tumors with MYC amplification.
  • The compound is currently undergoing Phase 1/2 clinical trials for safety and efficacy.

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