Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

  • J Med Chem. 2017 May 11;60(9):4002-4022. doi: 10.1021/acs.jmedchem.7b00306.
Léa Bouché  1 ,  Clara D Christ  1 ,  Stephan Siegel  1 ,  Amaury E Fernández-Montalván  1 ,  Simon J Holton  1 ,  Oleg Fedorov  2  3 ,  Antonius Ter Laak  1 ,  Tatsuo Sugawara  1 ,  Detlef Stöckigt  1 ,  Cynthia Tallant  2  3 ,  James Bennett  2  3 ,  Octovia Monteiro  2  3 ,  Laura Díaz-Sáez  2  3 ,  Paulina Siejka  2  3 ,  Julia Meier  2 ,  Vera Pütter  1 ,  Jörg Weiske  1 ,  Susanne Müller  2  3 ,  Kilian V M Huber  2  3 ,  Ingo V Hartung  1 ,  Bernard Haendler  1
Affiliations
  • 1. Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
  • 2. Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 3. Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
PMID: 28402630 DOI: 10.1021/acs.jmedchem.7b00306
Abstract

Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.

Products