The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.
RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.
Pamela A
PA
Haile
Bartholomew J
BJ
Votta
Robert W
RW
Marquis
Michael J
MJ
Bury
John F
JF
Mehlmann
Robert
R
Singhaus
Adam K
AK
Charnley
Ami S
AS
Lakdawala
Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre , Stevenage, SG1 2NY, UK.
Máire A
MA
Convery
David B
DB
Lipshutz
Biva M
BM
Desai
Barbara
B
Swift
Carol A
CA
Capriotti
Scott B
SB
Berger
Mukesh K
MK
Mahajan
Michael A
MA
Reilly
Elizabeth J
EJ
Rivera
Helen H
HH
Sun
Rakesh
R
Nagilla
Allison M
AM
Beal
Joshua N
JN
Finger
Michael N
MN
Cook
Bryan W
BW
King
Michael T
MT
Ouellette
Rachel D
RD
Totoritis
Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA) , 00196 Rome, Italy.
Maria
M
Pierdomenico
Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA) , 00196 Rome, Italy.
Anna
A
Negroni
Department of Cellular Biotechnology and Hematology, Sapienza University Hospital Umberto I , 00161 Rome, Italy.
Laura
L
Stronati
Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University Hospital Umberto I , 00161 Rome, Italy.
Salvatore
S
Cucchiara
Endoscopy Unit, Barts Health, Royal London Hospital , E1 1BB London, U.K.
Bartłomiej
B
Ziółkowski
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
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
Peter J
PJ
Gough
John
J
Bertin
Linda N
LN
Casillas
D000634:Aminoquinolines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*
D000634:Aminoquinolines; C000619430:GSK583; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2