A novel pan-selective bromodomain inhibitor for epigenetic drug design

Eur J Med Chem. 2023 Mar 5:249:115139. doi: 10.1016/j.ejmech.2023.115139. Epub 2023 Jan 25.

Abstract

For a long time, the development of bromodomain (BD) inhibitors (BDi) was almost exclusively related to the BET family. More recently, BDi for BDs outside the BET family have also been developed. Here we present a novel pan-BDi with micromolar affinities to various BDs, and nanomolar affinities to representatives of BD families I, II (Bromodomain and Extra-Terminal Domain (BET) family), III, and IV. The inhibitor shows a broad activity profile with nanomolar growth inhibition (GI50) values on various cancer cell lines. Subsequently, we were able to control the selectivity of the inhibitor by simple modifications and turned it into a highly selective BRD9 inhibitor.

Keywords: Bromodomain; Drug design; Epigenetics; MPM6; Pan-inhibitor.

MeSH terms

  • Cell Line
  • Drug Design*
  • Epigenesis, Genetic
  • Humans
  • Protein Domains
  • Transcription Factors* / metabolism

Substances

  • Transcription Factors
  • BRD9 protein, human