Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300

Bioorg Med Chem Lett. 2018 Jan 1;28(1):15-23. doi: 10.1016/j.bmcl.2017.11.025. Epub 2017 Nov 14.

Abstract

A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.

Keywords: Bromodomain; CBP inhibitor; Half-life; Volume of distribution.

MeSH terms

  • Animals
  • Binding Sites
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / metabolism
  • Cell Cycle Proteins
  • Crystallography, X-Ray
  • Drug Design*
  • Half-Life
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Dynamics Simulation
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / metabolism

Substances

  • BRD4 protein, human
  • Biphenyl Compounds
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • diphenyl
  • p300-CBP Transcription Factors