Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action

ACS Chem Biol. 2017 Nov 17;12(11):2730-2736. doi: 10.1021/acschembio.7b00708. Epub 2017 Oct 24.

Abstract

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors*
  • ATPases Associated with Diverse Cellular Activities / chemistry
  • ATPases Associated with Diverse Cellular Activities / metabolism*
  • Cell Line, Tumor
  • Chromatin / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Drug Discovery
  • Histones / metabolism
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Probes / chemistry*
  • Molecular Probes / pharmacology*
  • Protein Interaction Maps / drug effects*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Multimerization / drug effects*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Ligands
  • Molecular Probes
  • Protein Isoforms
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities