2. Academic Validation
  3. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains

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

Affiliation

  • 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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