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.

RIP2激酶(RIP2 kinase)是先天免疫系统(innate immune system)的核心组分，可在模式识别受体(pattern recognition receptors) NOD1与NOD2激活后介导下游信号通路，进而促进炎性细胞因子(inflammatory cytokines)的产生。近年来，多款RIP2激酶抑制剂被公开报道，为学界深入理解RIP2在该信号通路中的功能提供了重要支撑。然而，由于这些抑制剂要么缺乏广谱激酶选择性，要么对RIP2的结合亲和力不足，导致其在复杂生物环境中评估RIP2功能的实用价值极为有限。本文中，我们报道了新一代RIP2激酶抑制剂GSK583的发现及其药理学特性表征，该化合物兼具优异的选择性与强效活性。在证实该工具化合物的药理学精准性后，我们通过一系列体外、体内及离体实验阐明了RIP2激酶的功能，进一步明确了RIP2在NOD1与NOD2介导的疾病发病机制中的作用。