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.
Amaury E Fernández-Montalván  1 ,  Markus Berger  1 ,  Benno Kuropka  1 ,  Seong Joo Koo  1 ,  Volker Badock  1 ,  Joerg Weiske  1 ,  Vera Puetter  1 ,  Simon J Holton  1 ,  Detlef Stöckigt  1 ,  Antonius Ter Laak  1 ,  Paolo A Centrella  2 ,  Matthew A Clark  2 ,  Christoph E Dumelin  2 ,  Eric A Sigel  2 ,  Holly H Soutter  2 ,  Dawn M Troast  2 ,  Ying Zhang  2 ,  John W Cuozzo  2 ,  Anthony D Keefe  2 ,  Didier Roche  3 ,  Vincent Rodeschini  3 ,  Apirat Chaikuad  4  5 ,  Laura Díaz-Sáez  4  5 ,  James M Bennett  4  5 ,  Oleg Fedorov  4  5 ,  Kilian V M Huber  4  5 ,  Jan Hübner  1 ,  Hilmar Weinmann  1 ,  Ingo V Hartung  1 ,  Mátyás Gorjánácz  1
Affiliations
  • 1. Bayer AG , Pharmaceuticals, Drug Discovery, Berlin, Germany.
  • 2. X-Chem Pharmaceuticals , Waltham, Massachusetts United States.
  • 3. Edelris , Lyon, France.
  • 4. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford , Oxford, United Kingdom.
  • 5. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford , Oxford, United Kingdom.
PMID: 29043777 DOI: 10.1021/acschembio.7b00708
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.

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