GSK583 is an Orally Active and Selective RIP2 Kinase Inhibitor

In previous blogs, I have introduces several RIPK inhibitors, including RIP1 inhibitors RIPA-56, PK68, GSK547, GNE684, and GSK2982772. But the RIP2 inhibitors are lacked, today, I’d like to make up this. As we all known, RIPK1 is a critical driver of inflammation, involving in various pathways downstream of the death receptors, such as TNFR1, FasL, TRAIL, and toll-like receptors.

So, what is the role of RIP2?

RIP2 kinase is a vital component of the innate immune system. It also enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2 leading to the production of inflammatory cytokines. A study from Pamela A. Haile discovered and identified a RIP2 inhibitor GSK583, GSK583 is a highly potent and selective inhibitor of RIP2 Kinase, with IC50 of 5 nM.

In vitro, GSK583 (1 μM) exhibits excellent selectivity in a panel of 300 kinases, including p38α and VEGFR2. GSK583 potently and dose-dependently inhibits MDP-stimulated tumor necrosis factor-alpha (TNFα) production with an IC50 of 8 nM. GSK583 demonstrates only a modest reduction in potency when profiled in a similar MDP-induced TNFα production assay in human whole blood (IC50 = 237 nM) and rat whole blood (IC50 = 133 nM).

In vivo, GSK583 (0.1, 1, and 10 mg/kg, p.o.) inhibits serum KC levels in rats in a dose-dependent manner. Similarly, GSK583 inhibits serum KC levels and recruitment of neutrophils into the peritoneal cavity in mice in a dose-dependent manner. It exhibited an IC50 of 37 nM (15 ng/mL) derived from mouse blood concentration.

Haile PA et al. The Identification and Pharmacological Characterization of 6-(start-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.