title: 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: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors: Danilo
authors: D
authors: Froriep
authors: Bernd
authors: B
authors: Clement
authors: Florian
authors: F
authors: Bittner
authors: Ralf R
authors: RR
authors: Mendel
authors: Debora
authors: D
authors: Reichmann
authors: Wolfgang
authors: W
authors: Schmalix
authors: Antje
authors: A
authors: Havemeyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010091:Oximes; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism*; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D010091:Oximes; D010879:Piperazines; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D010649:Phenylalanine; D010088:Oxidoreductases; C554553:MTARC1 protein, human; C554552:mitochondrial amidoxime reducing component 2, human; C580590:upamostat; C487758:N-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(L)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride