Methylpyrrole inhibitors of BET bromodomains

Bioorg Med Chem Lett. 2017 May 15;27(10):2225-2233. doi: 10.1016/j.bmcl.2017.02.057. Epub 2017 Feb 24.

Abstract

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

Keywords: BET proteins; Bromodomain; Fragment screening.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Design
  • Half-Life
  • Humans
  • Mice
  • Molecular Dynamics Simulation
  • Multiple Myeloma / drug therapy
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacokinetics
  • Pyrroles / therapeutic use
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Brd4 protein, mouse
  • Nuclear Proteins
  • Pyrroles
  • Transcription Factors