title: Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A).
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.
authors.affiliation: Epinova DPU, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. jon.t.seal@gsk.com
authors.forename: Jonathan
authors.initials: J
authors.lastname: Seal
authors.forename: Yann
authors.initials: Y
authors.lastname: Lamotte
authors.forename: Frédéric
authors.initials: F
authors.lastname: Donche
authors.forename: Anne
authors.initials: A
authors.lastname: Bouillot
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Françoise
authors.initials: F
authors.lastname: Gellibert
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
authors.forename: Gael
authors.initials: G
authors.lastname: Krysa
authors.forename: Jorge
authors.initials: J
authors.lastname: Kirilovsky
authors.forename: Soren
authors.initials: S
authors.lastname: Beinke
authors.forename: Scott
authors.initials: S
authors.lastname: McCleary
authors.forename: Inma
authors.initials: I
authors.lastname: Rioja
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.forename: Toni
authors.initials: T
authors.lastname: Lewis
authors.forename: Ann L
authors.initials: AL
authors.lastname: Walker
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: David
authors.initials: D
authors.lastname: Lugo
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D007555:Isoxazoles; D009419:Nerve Tissue Proteins; D011804:Quinolines