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

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

  • Nat Med. 2016 Feb;22(2):202-9. doi: 10.1038/nm.4020.
Damian J Mole 1 2,  Scott P Webster 3,  Iain Uings 4,  Xiaozhong Zheng 1,  Margaret Binnie 3,  Kris Wilson 3,  Jonathan P Hutchinson 5,  Olivier Mirguet 6,  Ann Walker 4,  Benjamin Beaufils 6,  Nicolas Ancellin 6,  Lionel Trottet 6,  Véronique Bénéton 6,  Christopher G Mowat 7,  Martin Wilkinson 7,  Paul Rowland 5,  Carl Haslam 5,  Andrew McBride 3,  Natalie Z M Homer 8,  James E Baily 3,  Matthew G F Sharp 9,  O James Garden 2,  Jeremy Hughes 1,  Sarah E M Howie 1,  Duncan S Holmes 4,  John Liddle 4,  John P Iredale 1
Affiliations

Affiliations

  • 1 Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
  • 2 Clinical Surgery, University of Edinburgh, Edinburgh, UK.
  • 3 University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
  • 4 Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, UK.
  • 5 Molecular Discovery Research, GlaxoSmithKline, Stevenage, UK.
  • 6 Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
  • 7 EastChem School of Chemistry, University of Edinburgh, Edinburgh, UK.
  • 8 Mass Spectrometry Core, University of Edinburgh, Edinburgh, UK.
  • 9 Central Bioresearch Services, University of Edinburgh, Edinburgh, UK.
PMID: 26752518 DOI: 10.1038/nm.4020
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 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 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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