5MZC

Pseudomonas fluorescens kynurenine 3-monooxygenase (KMO) in complex with 3-(5-chloro-6-ethoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid

Summary for 5MZC

• Entry DOI: 10.2210/pdb5mzc/pdb
• Descriptor: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: kmo, oxidoreductase
• Biological source: Pseudomonas fluorescens
• Total number of polymer chains: 2
• Total formula weight: 104733.63

Authors

Rowland, P. (deposition date: 2017-01-31, release date: 2017-04-19, Last modification date: 2024-05-08)

Primary citation

Walker, A.L.,Ancellin, N.,Beaufils, B.,Bergeal, M.,Binnie, M.,Bouillot, A.,Clapham, D.,Denis, A.,Haslam, C.P.,Holmes, D.S.,Hutchinson, J.P.,Liddle, J.,McBride, A.,Mirguet, O.,Mowat, C.G.,Rowland, P.,Tiberghien, N.,Trottet, L.,Uings, I.,Webster, S.P.,Zheng, X.,Mole, D.J.
Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis.
J. Med. Chem., 60:3383-3404, 2017

PubMed Abstract: Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.

PubMed: 28398044
DOI: 10.1021/acs.jmedchem.7b00055

Experimental method

X-RAY DIFFRACTION (1.82 Å)