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

Jonathan P. Hutchinson, Paul Rowland, Mark R. D. Taylor, Erica M. Christodoulou, Carl Haslam, Clare I. Hobbs, Duncan S. Holmes, Paul Homes, John Liddle, Damian J. Mole, Iain Uings, Ann L. Walker, Scott P. Webster, Christopher G. Mowat and Chun-wa Chung ()
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Jonathan P. Hutchinson: Platform Technologies and Science, GlaxoSmithKline
Paul Rowland: Platform Technologies and Science, GlaxoSmithKline
Mark R. D. Taylor: EastChem School of Chemistry, University of Edinburgh
Erica M. Christodoulou: Platform Technologies and Science, GlaxoSmithKline
Carl Haslam: Platform Technologies and Science, GlaxoSmithKline
Clare I. Hobbs: Platform Technologies and Science, GlaxoSmithKline
Duncan S. Holmes: Discovery Partnerships with Academia, GlaxoSmithKline
Paul Homes: Platform Technologies and Science, GlaxoSmithKline
John Liddle: Discovery Partnerships with Academia, GlaxoSmithKline
Damian J. Mole: Medical Research Council Centre for Inflammation Research
Iain Uings: Discovery Partnerships with Academia, GlaxoSmithKline
Ann L. Walker: Discovery Partnerships with Academia, GlaxoSmithKline
Scott P. Webster: Centre for Cardiovascular Science, University of Edinburgh
Christopher G. Mowat: EastChem School of Chemistry, University of Edinburgh
Chun-wa Chung: Platform Technologies and Science, GlaxoSmithKline

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington’s and Alzheimer’s. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

Date: 2017
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DOI: 10.1038/ncomms15827

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