Title
Discovery and SAR of novel and selective inhibitors of urokinase plasminogen activator (uPA) with an imidazo[1,2-a]pyridine scaffold
Author
Faculty/Department
Faculty of Sciences. Biology
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
58(2015) :23 , p. 9238-9257
ISSN
0022-2623
ISI
000366340000012
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's Si pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-a]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design.
E-info
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https://repository.uantwerpen.be/docman/iruaauth/309f00/130213.pdf
Full text (open access)
https://repository.uantwerpen.be/docman/irua/2cc3af/129222_2016_12_01.pdf
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