Systemic tryptophan metabolism in mammals occurs primarily via the kynurenine pathway. Tryptophan metabolites contribute to acute lung injury in rats with AP. The blood in humans with severe AP shows elevation of the tryptophan metabolite kynurenine. Kynurenine-3-monooxygenase (KMO) is a key enzyme of tryptophan metabolism, and it increases oxidative stress, induces apoptosis and is injurious to several cell types. Meanwhile, it is central to the pathogenesis of acute pancreatitis (AP)-multiple organ dysfunction syndrome (MODS). Inhibition of KMO should reduce 3–hydroxykynurenine production. Thus, it may provide an efficacious strategy to prevent or reduce the severity of extrapancreatic organ injury in AP. GSK180 is a selective, competitive, and potent inhibitor of KMO with an IC50 of ~6 nM.
GSK180 decreases as the concentration of kynurenine are increased. Therefore, it shows the inhibition by GSK180 is competitive with the kynurenine substrate. Furthermore, GSK180 shows negligible activity against other enzymes on the tryptophan pathway, against a panel of over 50 unrelated proteins and against an additional series of acidergic proteins. GSK180 has a mean IC50 of 2 µM in a cell-based assay. In addition, Primary human hepatocytes express endogenous KMO activity, GSK180 inhibits this activity with comparable potency (IC50=2.6 µM).
In vivo, GSK180 results in rapid changes in the levels of kynurenine pathway metabolites. Besides, it affords therapeutic protection against MODS in a rat model of AP.
All in all, KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and open up a new area for drug discovery in critical illness. GSK180 remains a useful tool to probe the therapeutic potential of KMO inhibition.