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Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using

Ashvinikumar V Gavai1, Derek Norris1, George Delucca1

  • 1Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.

Journal of Medicinal Chemistry
|September 20, 2021
PubMed

Insights

Researchers developed BMS-986158, a potent inhibitor targeting bromodomain and extra-terminal (BET) proteins. This drug candidate shows promise for treating various cancers by regulating oncogene transcription.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Bromodomain and extra-terminal (BET) proteins regulate oncogene transcription, making them therapeutic targets.
  • Inhibiting BET proteins offers a strategy for cancer treatment, particularly for oncogenes like c-MYC.

Purpose of the Study:

  • To discover and optimize novel inhibitors of BET proteins.
  • To develop a potent and pharmacokinetically favorable BET inhibitor for clinical evaluation.

Main Methods:

  • Structure-activity relationship (SAR) studies and protein structure-guided drug design were employed.
  • Screening identified initial hit compounds, followed by iterative optimization.
  • Binding affinity, functional assays, and pharmacokinetic profiling were performed.

Main Results:

  • A novel carbazole derivative (compound 9) showed improved binding to the conserved WPF shelf of BET proteins.
  • Further optimization led to compound 18 (BMS-986158) with high potency and favorable pharmacokinetic properties.
  • BMS-986158 demonstrated robust in vivo activity in hematologic and solid tumor models.

Conclusions:

  • BMS-986158 is a potent BET inhibitor with excellent drug-like properties.
  • Its favorable profile supports its selection as a clinical candidate for cancer therapy.

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