title: Design, synthesis, biochemical studies, cellular characterization, and structure-based computational studies of small molecules targeting the urokinase receptor.
abstract: The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR·uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis.
authors: Indiana University, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors: Fang
authors: F
authors: Wang
authors: W
authors: W
authors: Eric Knabe
authors: Liwei
authors: L
authors: Li
authors: Inha
authors: I
authors: Jo
authors: Timmy
authors: T
authors: Mani
authors: Hartmut
authors: H
authors: Roehm
authors: Kyungsoo
authors: K
authors: Oh
authors: Jing
authors: J
authors: Li
authors: May
authors: M
authors: Khanna
authors: Samy O
authors: SO
authors: Meroueh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D037241:Mannose-Binding Lectins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D008970:Molecular Weight; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C571689:2-((3-(3,5-dimethylpiperidin-1-yl)-6-oxo-6H-anthra(1,9-cd)isoxazol-5-yl)amino)benzoic acid; D000970:Antineoplastic Agents; D001565:Benzoates; C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D010880:Piperidines; D011956:Receptors, Cell Surface