Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Abstract

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish 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.

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

“…The majority share a common pharmacophore containing both an acidic moiety and a mono or 1,2-dichloro substitution of the core phenyl ring, including our previously reported oxazolidinone molecule, GSK180(A1)6. Replacement of one chlorine by methyl gave GSK428(A2), which showed a more attractive overall profile1920.…”

“…Recently, we demonstrated the beneficial role of KMO inhibition in the pathogenesis of acute pancreatitis6. This disease is typically caused by gallstones or excessive alcohol consumption.…”

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

“…In addition, KMO is central to the pathogenesis of acute-pancreatitis-multiple organ dysfunction syndrome (MODS). KMO inhibition by genetic deletion or a potent and specific inhibitor, oxazolidinone GSK180 (3-(5,6-dichloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid), prevents extrapancreatic tissue injury to the lung, kidney and liver in mouse model of acute-pancreatitis (Table 3), may through upregulation of Kyn, KA, and AA, or downregulation of 3-HK and 3-HAA [154]. Therefore, KMO inhibition may prevent inflammation-related CVD including atherosclerosis and AAA.…”

Identifying risk factors for progression to critical care admission and death among individuals with acute pancreatitis: a record linkage analysis of Scottish healthcare databases

“…Given the substantial healthcare burden of AP, the need for improved understanding and treatment of AP and the considerable interest in the development of novel therapies for AP by us 15 and others, the aim of this study was to harness the power of the Farr Institute capabilities to elucidate the epidemiology of AP with a focus on defining the risk factors for the development of organ failure in AP.…”