2. Academic Validation
  3. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

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

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.

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