Activation of the anti-cancer agent upamostat by the mARC enzyme system.

Abstract	Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b₅ and NADH cytochrome b₅ reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat.
Authors	Danilo Froriep, Bernd Clement, Florian Bittner, Ralf R Mendel, Debora Reichmann, Wolfgang Schmalix, Antje Havemeyer
Journal	Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 43 Issue 9 Pg. 780-4 (Sep 2013) ISSN: 1366-5928 [Electronic] England
PMID	23379481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Mitochondrial Proteins Oximes Piperazines Recombinant Fusion Proteins Sulfonamides Phenylalanine Oxidoreductases mitochondrial amidoxime reducing component 1, human mitochondrial amidoxime reducing component 2, human upamostat N-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(L)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride
Topics	Animals Antineoplastic Agents (metabolism) Chromatography, High Pressure Liquid Enzyme Activation Humans Mitochondrial Proteins (metabolism) Oxidation-Reduction Oxidoreductases (metabolism) Oximes Phenylalanine (analogs & derivatives, metabolism) Piperazines (metabolism) Recombinant Fusion Proteins (metabolism) Sulfonamides (metabolism) Swine

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