2. Academic Validation
  3. Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

  • ACS Med Chem Lett. 2013 Jul 16;4(9):835-40. doi: 10.1021/ml4001485.
Victor S Gehling 1,  Michael C Hewitt 1,  Rishi G Vaswani 1,  Yves Leblanc 1,  Alexandre Côté 1,  Christopher G Nasveschuk 1,  Alexander M Taylor 1,  Jean-Christophe Harmange 1,  James E Audia 1,  Eneida Pardo 1,  Shivangi Joshi 1,  Peter Sandy 1,  Jennifer A Mertz 1,  Robert J Sims 3rd 1,  Louise Bergeron 1,  Barbara M Bryant 1,  Steve Bellon 1,  Florence Poy 1,  Hariharan Jayaram 1,  Ravichandran Sankaranarayanan 2,  Sreegouri Yellapantula 2,  Nandana Bangalore Srinivasamurthy 2,  Swarnakumari Birudukota 2,  Brian K Albrecht 1
Affiliations

Affiliations

  • 1 Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
  • 2 Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwantpur, Bangalore 560 022, India.
PMID: 24900758 DOI: 10.1021/ml4001485
Abstract

The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.

Keywords

BET inhibitors; MYC; bromodomain; fragments; isoxazoles.

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