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

Authors: Mole, DJ  Webster, SP  Uings, I  Zheng, X  Binnie, M  Wilson, K  Hutchinson, JP  Mirguet, O  Walker, A  Beaufils, B  Ancellin, N  Trottet, L  Beneton, V  Mowat, CG  Wilkinson, M  Rowland, P  Haslam, C  McBride, A  Homer, NZ  Baily, JE  Sharp, MG  Garden, OJ  Hughes, J  Howie, SE  Holmes, DS  Liddle, J  Iredale, JP 
Citation: Mole DJ, etal., Nat Med. 2016 Feb;22(2):202-9. doi: 10.1038/nm.4020. Epub 2016 Jan 11.
Pubmed: (View Article at PubMed) PMID:26752518
DOI: Full-text: DOI:10.1038/nm.4020

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 death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone 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 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

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CRRD Object Information
CRRD ID: 11342439
Created: 2016-07-06
Species: All species
Last Modified: 2016-07-06
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.