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
  • 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.