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Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A) |
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| Authors: | Seal Jonathan Lamotte Yann Donche Frédéric Bouillot Anne Mirguet Olivier Gellibert Françoise Nicodeme Edwige Krysa Gael Kirilovsky Jorge Beinke Soren McCleary Scott Rioja Inma Bamborough Paul Chung Chun-Wa Gordon Laurie Lewis Toni Walker Ann L Cutler Leanne Lugo David Wilson David M Witherington Jason Lee Kevin Prinjha Rab K |
| Affiliation: | Epinova DPU, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. jon.t.seal@gsk.com |
| Abstract: | A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model. |
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