title: DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.
abstract: The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.
authors: Philip A
authors: PA
authors: Harris
authors: Bryan W
authors: BW
authors: King
authors: Deepak
authors: D
authors: Bandyopadhyay
authors: Scott B
authors: SB
authors: Berger
authors: Nino
authors: N
authors: Campobasso
authors: Carol A
authors: CA
authors: Capriotti
authors: Julie A
authors: JA
authors: Cox
authors: Lauren
authors: L
authors: Dare
authors: Xiaoyang
authors: X
authors: Dong
authors: Joshua N
authors: JN
authors: Finger
authors: Platform Technology & Science, GlaxoSmithKline , Winter Street, Waltham, Massachusetts 02451, United States.
authors: LaShadric C
authors: LC
authors: Grady
authors: Sandra J
authors: SJ
authors: Hoffman
authors: Jae U
authors: JU
authors: Jeong
authors: James
authors: J
authors: Kang
authors: Viera
authors: V
authors: Kasparcova
authors: Ami S
authors: AS
authors: Lakdawala
authors: Ruth
authors: R
authors: Lehr
authors: Dean E
authors: DE
authors: McNulty
authors: Rakesh
authors: R
authors: Nagilla
authors: Michael T
authors: MT
authors: Ouellette
authors: Christina S
authors: CS
authors: Pao
authors: Alan R
authors: AR
authors: Rendina
authors: Michelle C
authors: MC
authors: Schaeffer
authors: Platform Technology & Science, GlaxoSmithKline , Winter Street, Waltham, Massachusetts 02451, United States.
authors: Jennifer D
authors: JD
authors: Summerfield
authors: Barbara A
authors: BA
authors: Swift
authors: Rachel D
authors: RD
authors: Totoritis
authors: Paris
authors: P
authors: Ward
authors: Platform Technology & Science, GlaxoSmithKline , King of Prussia, Pennsylvania 19406, United States.
authors: Aming
authors: A
authors: Zhang
authors: Daohua
authors: D
authors: Zhang
authors: Robert W
authors: RW
authors: Marquis
authors: John
authors: J
authors: Bertin
authors: Peter J
authors: PJ
authors: Gough
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: C000609790:GSK'481; D007555:Isoxazoles; D010077:Oxazepines; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D004247:DNA; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse