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% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population4. 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 metabolism5, 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 Å 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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Acknowledgements
D.J.M. is supported by a Clinician Scientist Fellowship from the Health Foundation/Academy of Medical Sciences, the Medical Research Council Developmental Pathway Funding Stream and Wellcome Trust Institutional Strategic Support Fund. J.P.I. acknowledges the support of the Medical Research Council. We thank D. Harbison, Edinburgh Bioquarter, the staff of the Central Bioresearch Services, University of Edinburgh; F. Howie, D. Mauchline, M. McMillan, L. Boswell and M. Millar; and colleagues in the Medical Research Council Centre for Inflammation Research for support and advice.
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D.J.M., S.P.W., I.U. and J.L. led the University of Edinburgh/GlaxoSmithKline Discovery Partnership with Academia collaboration. D.J.M., S.P.W., I.U., O.J.G., J.P.H., S.E.M.H., D.S.H., J.L. and J.P.I. developed and refined the hypothesis and experimental design. D.J.M., X.Z., I.U., B.B., N.A., L.T. and V.B. did or designed the in vivo experiments. X.Z., M.G.F.S. and D.J.M. made the genetically altered mice from iKOMP embryonic stem cells. J.E.B. reported the pathology. S.P.W., I.U., J.L., M.B. and K.W. did or designed the cell-based experiments. N.Z.M.H., S.P.W. and M.B. did or developed the LC-MS/MS. J.P.H., C.H., J.L., S.P.W., D.J.M., A.M., I.U. and D.S.H. did or designed the assay development and screening. O.M., A.W., J.L., J.H. and D.S.H. did or designed the medicinal chemistry. P.R., C.G.M. and M.W. did the structural biology. All authors contributed to data analysis and/or interpretation. All authors contributed to, revised and approved the final version of the manuscript.
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The University of Edinburgh is engaged in a Discovery Partnership with Academia collaboration with GlaxoSmithKline. The University of Edinburgh receives milestone and royalty payments according to the phase of the project, as governed by the University of Edinburgh revenue sharing policy.
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Mole, D., Webster, S., Uings, I. et al. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. Nat Med 22, 202–209 (2016). https://doi.org/10.1038/nm.4020
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DOI: https://doi.org/10.1038/nm.4020
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