Biochem/physiol Actions

GSK583 is a cell-permeable indazolylquinolinamine that acts as an ATP-competitive (IC50 = 2 & 5 nM using rat & human RIPK2, respectively) inhibitor against RIPK2 kinase activity (66.6% inhibition at 1 µM; [ATP] = 10 µM), exhibiting much reduced or no inhibitory potency against a panel of 209 other kinases ﹤34% inhibition at 1 µM; [ATP] = 10 ?M). GSK583 selectively inhibits against NOD1- and NOD2-, but not TLR2-, TLR4-, TLR7-. IL-1R-, or TNFR-dependent pro-inflammatory cytokines release (>95% inhibition vs. ﹤40% inhibition at 1 ?M using primary human monocytes stimulated with respective ligands). GSK583 effectively inhibits TNF? and IL-6 production from Crohn′s disease (CD) and ulcerative colitis (UC) patients intestinal explant cultures ex vivo (IC50 = 200 nM) and is efficacious against NOD1 ligand FK156- and NOD2 ligand MDP-induced inflammatory responses in mice and rats (10 mg/kg p.o.) in vivo.