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 (nucleotide-binding oligomerization domain-containing proteins 1 and 2), leading to the production of inflammatory cytokines. GSK583 is a highly effective and selective RIP2 kinase inhibitor with IC50 value of 5 nM. GSK583 exhibited excellent selectivity in a panel of 300 kinases at 1 μM compound concentration. In this panel, only RIP2 was inhibited >50% by GSK583 and only two additional kinases were inhibited by approximately 30% (BRK, Aurora A). Following treatment with GSK583 at 1 μM, complete inhibition was observed upon activation of both NOD1 and NOD2 receptors, which signal in a RIP2-dependent manner. The pharmacokinetic parameters of GSK583 are consistent across rodent species exemplifying low clearance, moderate volumes of distribution, and moderate oral bioavailability. A combination of models which measured local and systemic inflammatory responses to intraperitoneal injection of L18-MDP in mice and intravenous injection of L18-MDP in rats with oral doses of GSK583 of 0.1, 1, and 10 mg/kg was employed to demonstrate the utility of GSK583. It inhibited serum KC (the rodent orthologue of IL-8) levels in rats in a dose-dependent manner, with an IC50 derived from rat blood concentrations of 50 nM (or 20 ng/mL). Similarly, it inhibited serum KC levels (data not shown) and recruitment of neutrophils into the peritoneal cavity in mice in a dose-dependent manner, with an IC50 of 37 nM (15 ng/mL) derived from mouse blood concentrations. As expected, a single oral dose of 10 mg/kg of GSK583 also inhibited the increase in serum levels of KC following administration of the NOD1 ligand, FK156 in mice[2].
作用机制
GSK583 binds to the human RIP2 catalytic domain (res 1–310)[2].
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