title: Virtual screening targeting the urokinase receptor, biochemical and cell-based studies, synthesis, pharmacokinetic characterization, and effect on breast tumor metastasis.
abstract: Virtual screening targeting the urokinase receptor (uPAR) led to (±)-3-(benzo[d][1,3]dioxol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-phenylbutan-1-amine 1 (IPR-1) and N-(3,5-dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide 3 (IPR-69). Synthesis of an analogue of 1, namely, 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC(50) near 30 μM. Both compounds blocked angiogenesis with IC(50) of 3 μM. Compounds 2 and 3 inhibited cell growth with IC(50) of 6 and 18 μM and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 h. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Sinn
authors.forename: W Eric
authors.initials: WE
authors.lastname: Knabe
authors.forename: May
authors.initials: M
authors.lastname: Khanna
authors.forename: Inha
authors.initials: I
authors.lastname: Jo
authors.forename: Jayne M
authors.initials: JM
authors.lastname: Silver
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Oh
authors.forename: Liwei
authors.initials: L
authors.lastname: Li
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Karen E
authors.initials: KE
authors.lastname: Pollok
authors.forename: Samy O
authors.initials: SO
authors.lastname: Meroueh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D000813:Anilides; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; C568954:N-(3,5-dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide; D011720:Pyrazoles; D055293:Receptors, Urokinase Plasminogen Activator