The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the combination of WX-UK1 and capecitabine in patients with advanced malignancies.

Start Date01 May 2004

Sponsor / Collaborator

Heidelberg Pharma AG

[+1]

100 Clinical Results associated with WX-UK1

100 Translational Medicine associated with WX-UK1

100 Patents (Medical) associated with WX-UK1

Literatures (Medical) associated with WX-UK1

02 Dec 2023·Expert Opinion on Investigational Drugs

Upamostat: a serine protease inhibitor for antiviral, gastrointestinal, and anticancer indications

Review

Author: Plasse, TF. ; Fathi, R. ; Fehrmann, C. ; McComsey, GA.

INTRODUCTIONSerine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes.AREAS COVEREDResearch over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months.EXPERT OPINIONUpamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.

07 Apr 2016·OncogeneQ1 · MEDICINE

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

Q1 · MEDICINE

Article

Author: Moilanen, A ; Klefström, J ; Ala-Hongisto, H ; Nevalaita, L ; Joensuu, H ; Englund, J I ; Leidenius, M ; Pant, S M ; Kovanen, P E ; Belitškin, D ; Sihto, H ; Ramachandra, M ; Poso, A ; Hewitson, K ; Heikkilä, P ; Tervonen, T A ; Marques, E

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

01 Sep 2013·XenobioticaQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Danilo Froriep ; Antje Havemeyer ; Bernd Clement ; Ralf R. Mendel ; Wolfgang Schmalix ; Florian Bittner ; Debora Reichmann

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.

100 Deals associated with WX-UK1

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 2	US	Heidelberg Pharma AG	01 May 2004
Neoplasms	Phase 2	-	Wilex GmbH Im- u. Export von Investitions- und Verbrauchsgüter	-
Neoplasms	Phase 2	-	Wilex GmbH Im- u. Export von Investitions- und Verbrauchsgüter	-
Solid tumor	Phase 2	DE	Wilex, Inc.	-

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