title: Small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo.
abstract: FAK is a tyrosine kinase that functions as a key orchestrator of signals leading to invasion and metastasis. Since FAK interacts directly with a number of critical proteins involved in survival signaling in tumor cells, we hypothesized that targeting a key protein-protein interface with druglike small molecules was a feasible strategy for inhibiting tumor growth. In this study, we targeted the protein-protein interface between FAK and VEGFR-3 and identified compound C4 (chloropyramine hydrochloride) as a drug capable of (1) inhibiting the biochemical function of VEGFR-3 and FAK, (2) inhibiting proliferation of a diverse set of cancer cell types in vitro, and (3) reducing tumor growth in vivo. Chloropyramine hydrochloride reduced tumor growth as a single agent, while concomitant administration with doxorubicin had a pronounced synergistic effect. Our data demonstrate that the FAK-VEGFR-3 interaction can be targeted by small druglike molecules and this interaction can provide the basis for highly specific novel cancer therapeutics.
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kurenova
authors.forename: Darell L
authors.initials: DL
authors.lastname: Hunt
authors.forename: Dihua
authors.initials: D
authors.lastname: He
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Magis
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D005029:Ethylenediamines; C004664:chloropyramine; D040321:Vascular Endothelial Growth Factor Receptor-3; D051416:Focal Adhesion Protein-Tyrosine Kinases