Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1804-1810. doi: 10.1016/j.bmcl.2018.04.020. Epub 2018 Apr 11.

Abstract

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Mice
  • Microsomes / metabolism
  • Molecular Dynamics Simulation
  • Multiple Myeloma / drug therapy
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Pyridones / chemistry*
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Pyridones
  • Transcription Factors