Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Philip A
0000-0002-5189-3326
PA
Harris
Scott B
SB
Berger
Jae U
JU
Jeong
Rakesh
R
Nagilla
Deepak
D
Bandyopadhyay
Nino
N
Campobasso
Carol A
CA
Capriotti
Julie A
JA
Cox
Lauren
L
Dare
Xiaoyang
X
Dong
Patrick M
PM
Eidam
Joshua N
JN
Finger
Sandra J
SJ
Hoffman
James
J
Kang
Viera
V
Kasparcova
Bryan W
BW
King
Ruth
R
Lehr
Yunfeng
Y
Lan
Lara K
LK
Leister
John D
JD
Lich
Centre for Immunobiology, Blizard Institute, Barts, and The London School of Medicine and Dentistry, Queen Mary University of London , E1 2AD London, U.K.
Thomas T
TT
MacDonald
Nathan A
NA
Miller
Michael T
MT
Ouellette
Christina S
CS
Pao
Attiq
A
Rahman
Michael A
MA
Reilly
Alan R
AR
Rendina
Elizabeth J
EJ
Rivera
Michelle C
MC
Schaeffer
Clark A
CA
Sehon
Robert R
RR
Singhaus
Helen H
HH
Sun
Barbara A
BA
Swift
Rachel D
RD
Totoritis
Centre for Immunobiology, Blizard Institute, Barts, and The London School of Medicine and Dentistry, Queen Mary University of London , E1 2AD London, U.K.
Anna
A
Vossenkämper
Paris
P
Ward
David D
DD
Wisnoski
Daohua
D
Zhang
Robert W
RW
Marquis
Peter J
PJ
Gough
John
J
Bertin
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001552:Benzazepines; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases