Discovery of a PCAF Bromodomain Chemical Probe

Angew Chem Int Ed Engl. 2017 Jan 16;56(3):827-831. doi: 10.1002/anie.201610816. Epub 2016 Dec 14.

Abstract

The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.

Keywords: bromodomains; chemical probes; epigenetics; medicinal chemistry; structure-based design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azo Compounds / chemical synthesis
  • Azo Compounds / chemistry
  • Azo Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hydralazine / chemical synthesis
  • Hydralazine / chemistry
  • Hydralazine / pharmacology*
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship
  • p300-CBP Transcription Factors / antagonists & inhibitors*

Substances

  • Azo Compounds
  • Molecular Probes
  • Hydralazine
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor