5J79

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, Compound 3 complex

Summary for 5J79

• Entry DOI: 10.2210/pdb5j79/pdb
• Related: 5J7B
• Descriptor: Receptor-interacting serine/threonine-protein kinase 2, 4-methyl-3-{[6-(methylsulfonyl)quinolin-4-yl]amino}phenol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase domain, kinase inhibitor, structure-based drug design, inhibitor selectivity, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : O43353
• Total number of polymer chains: 2
• Total formula weight: 76349.05

Authors

Convery, M.A.,Casillas, L.N.,Haile, P.A.,Votta, B.J.,Lakdawala, A.S. (deposition date: 2016-04-06, release date: 2016-05-18, Last modification date: 2023-09-27)

Primary citation

Haile, P.A.,Votta, B.J.,Marquis, R.W.,Bury, M.J.,Mehlmann, J.F.,Singhaus, R.,Charnley, A.K.,Lakdawala, A.S.,Convery, M.A.,Lipshutz, D.B.,Desai, B.M.,Swift, B.,Capriotti, C.A.,Berger, S.B.,Mahajan, M.K.,Reilly, M.A.,Rivera, E.J.,Sun, H.H.,Nagilla, R.,Beal, A.M.,Finger, J.N.,Cook, M.N.,King, B.W.,Ouellette, M.T.,Totoritis, R.D.,Pierdomenico, M.,Negroni, A.,Stronati, L.,Cucchiara, S.,Ziokowski, B.,Vossenkamper, A.,MacDonald, T.T.,Gough, P.J.,Bertin, J.,Casillas, L.N.
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., 59:4867-4880, 2016

PubMed 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.

PubMed: 27109867
DOI: 10.1021/acs.jmedchem.6b00211

Experimental method

X-RAY DIFFRACTION (2.69 Å)