Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains

  • J Med Chem. 2013 Oct 10;56(19):7501-15. doi: 10.1021/jm401088k.
Olivier Mirguet  1 ,  Romain Gosmini ,  Jérôme Toum ,  Catherine A Clément ,  Mélanie Barnathan ,  Jean-Marie Brusq ,  Jacqueline E Mordaunt ,  Richard M Grimes ,  Miriam Crowe ,  Olivier Pineau ,  Myriam Ajakane ,  Alain Daugan ,  Phillip Jeffrey ,  Leanne Cutler ,  Andrea C Haynes ,  Nicholas N Smithers ,  Chun-wa Chung ,  Paul Bamborough ,  Iain J Uings ,  Antonia Lewis ,  Jason Witherington ,  Nigel Parr ,  Rab K Prinjha ,  Edwige Nicodème
Affiliations
  • 1. Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.
PMID: 24015967 DOI: 10.1021/jm401088k
Abstract

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and Other cancers.

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