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
  • 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.

Products