Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

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 bioc...

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Veröffentlicht in:ACS Med. Chem. Lett 2013-09, Vol.4 (9), p.835-840
Hauptverfasser: Gehling, Victor S, Hewitt, Michael C, Vaswani, Rishi G, Leblanc, Yves, Côté, Alexandre, Nasveschuk, Christopher G, Taylor, Alexander M, Harmange, Jean-Christophe, Audia, James E, Pardo, Eneida, Joshi, Shivangi, Sandy, Peter, Mertz, Jennifer A, Sims, Robert J, Bergeron, Louise, Bryant, Barbara M, Bellon, Steve, Poy, Florence, Jayaram, Hariharan, Sankaranarayanan, Ravichandran, Yellapantula, Sreegouri, Bangalore Srinivasamurthy, Nandana, Birudukota, Swarnakumari, Albrecht, Brian K
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Sprache:eng
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Letter
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Zusammenfassung: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml4001485