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Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.

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.

SUBMITTER: Gehling VS

PROVIDER: S-EPMC4027525 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.

Gehling Victor S VS Hewitt Michael C MC Vaswani Rishi G RG Leblanc Yves Y Côté Alexandre A Nasveschuk Christopher G CG Taylor Alexander M AM Harmange Jean-Christophe JC Audia James E JE Pardo Eneida E Joshi Shivangi S Sandy Peter P Mertz Jennifer A JA Sims Robert J RJ Bergeron Louise L Bryant Barbara M BM Bellon Steve S Poy Florence F Jayaram Hariharan H Sankaranarayanan Ravichandran R Yellapantula Sreegouri S Bangalore Srinivasamurthy Nandana N Birudukota Swarnakumari S Albrecht Brian K BK

ACS medicinal chemistry letters 20130716 9

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. ...[more]

PMID: 24900758

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