2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 May 26;59(10):4867-80. doi: 10.1021/acs.jmedchem.6b00211.
Pamela A Haile,  Bartholomew J Votta,  Robert W Marquis,  Michael J Bury,  John F Mehlmann,  Robert Singhaus Jr,  Adam K Charnley,  Ami S Lakdawala,  Máire A Convery 1,  David B Lipshutz,  Biva M Desai,  Barbara Swift,  Carol A Capriotti,  Scott B Berger,  Mukesh K Mahajan,  Michael A Reilly,  Elizabeth J Rivera,  Helen H Sun,  Rakesh Nagilla,  Allison M Beal,  Joshua N Finger,  Michael N Cook,  Bryan W King,  Michael T Ouellette,  Rachel D Totoritis,  Maria Pierdomenico 2,  Anna Negroni 2,  Laura Stronati 3,  Salvatore Cucchiara 4,  Bartłomiej Ziółkowski 5,  Anna Vossenkämper 6,  Thomas T MacDonald 6,  Peter J Gough,  John Bertin,  Linda N Casillas
Affiliations

Affiliations

  • 1 Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre , Stevenage, SG1 2NY, UK.
  • 2 Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA) , 00196 Rome, Italy.
  • 3 Department of Cellular Biotechnology and Hematology, Sapienza University Hospital Umberto I , 00161 Rome, Italy.
  • 4 Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University Hospital Umberto I , 00161 Rome, Italy.
  • 5 Endoscopy Unit, Barts Health, Royal London Hospital , E1 1BB London, U.K.
  • 6 Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , E1 2AD London, U.K.
PMID: 27109867 DOI: 10.1021/acs.jmedchem.6b00211
Abstract

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.

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