Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors

J Med Chem. 2015 Aug 13;58(15):6151-78. doi: 10.1021/acs.jmedchem.5b00773. Epub 2015 Jul 31.

Abstract

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adenosine Triphosphatases / chemistry
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / chemistry
  • Models, Molecular
  • Molecular Structure
  • Naphthyridines / chemistry*
  • Naphthyridines / pharmacology*

Substances

  • DNA-Binding Proteins
  • Naphthyridines
  • Adenosine Triphosphatases
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities