title: Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.
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 S1 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.
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Gladysz
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Adriaenssens
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: De Winter
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C000601654:2-(1H-imidazol-2-yl)pyridine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014568:Urokinase-Type Plasminogen Activator