| Literature DB >> 27109867 |
Pamela A Haile, Bartholomew J Votta, Robert W Marquis, Michael J Bury, John F Mehlmann, Robert Singhaus, Adam K Charnley, Ami S Lakdawala, Máire A Convery1, 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 Pierdomenico2, Anna Negroni2, Laura Stronati3, Salvatore Cucchiara4, Bartłomiej Ziółkowski5, Anna Vossenkämper6, Thomas T MacDonald6, Peter J Gough, John Bertin, Linda N Casillas.
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.Entities:
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Year: 2016 PMID： 27109867 DOI： 10.1021/acs.jmedchem.6b00211
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446