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J Med Chem. 2016 Feb 25;59(4):1634-41. doi: 10.1021/acs.jmedchem.5b01708. Epub 2016 Jan 6.

Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins.

Author information

1
Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
2
Department of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod , Gagarina av. 23, Nizhni Novgorod 603950, Russia.
3
Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université , 13288 Marseille, France.
4
Cisbio Bioassays, R&D , Parc Marcel Boiteux, BP 84175, 30200 Codolet, France.
5
Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
6
Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
7
Goethe-University , Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Science, Campus Riedberg, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.

Abstract

A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure-based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes.

PMID:
26735842
DOI:
10.1021/acs.jmedchem.5b01708
[Indexed for MEDLINE]

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