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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-05-04 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00211 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 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-05-04 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00211 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 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
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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.
中文翻译：
RIP2 激酶的高效选择性抑制剂 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583) 的鉴定和药理学表征
RIP2 激酶是先天免疫系统的核心成分，在模式识别受体 NOD1 和 NOD2 激活后能够实现下游信号传导，从而导致炎性细胞因子的产生。最近，已经公开了几种 RIP2 激酶抑制剂，它们有助于从根本上理解 RIP2 在该途径中的作用。然而，由于它们缺乏广泛的激酶选择性或对 RIP2 的强亲和力，这些工具在评估 RIP2 在复杂环境中的作用方面的效用有限。我们在此介绍了 GSK583 的发现和药理学特性，这是一种具有出色选择性和效力的下一代 RIP2 抑制剂。证明了这种工具化合物的药理精度，
更新日期：2016-05-04
中文翻译：
RIP2 激酶的高效选择性抑制剂 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583) 的鉴定和药理学表征
RIP2 激酶是先天免疫系统的核心成分，在模式识别受体 NOD1 和 NOD2 激活后能够实现下游信号传导，从而导致炎性细胞因子的产生。最近，已经公开了几种 RIP2 激酶抑制剂，它们有助于从根本上理解 RIP2 在该途径中的作用。然而，由于它们缺乏广泛的激酶选择性或对 RIP2 的强亲和力，这些工具在评估 RIP2 在复杂环境中的作用方面的效用有限。我们在此介绍了 GSK583 的发现和药理学特性，这是一种具有出色选择性和效力的下一代 RIP2 抑制剂。证明了这种工具化合物的药理精度，
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