title: Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer.
abstract: Preliminary studies in our laboratory have demonstrated the importance of both the NH2 and COOH terminus scaffolding functions of focal adhesion kinase (FAK). Here, we describe a new small molecule inhibitor, C10, that targets the FAK C-terminus scaffold. C10 showed marked selectivity for cells overexpressing VEGFR3 when tested in isogenic cell lines, MCF7 and MCF7-VEGFR3. C10 preferentially inhibited pancreatic tumor growth in vivo in cells with high FAK-Y925 and VEGFR3 expression. Treatment with C10 led to a significant inhibition in endothelial cell proliferation and tumor endothelial and lymphatic vessel density and decrease in interstitial fluid pressure. These results highlight the underlying importance of targeting the FAK scaffold to treat human cancers.
authors: Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Priyanka N
authors: PN
authors: Gogate
authors: Department of Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; CureFAKtor Pharmaceuticals, 14 Rockdove Lane, Orchard Park, NY 14127, USA.
authors: Elena V
authors: EV
authors: Kurenova
authors: Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Manivannan
authors: M
authors: Ethirajan
authors: Department of Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Jianqun
authors: J
authors: Liao
authors: Department of Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Michael
authors: M
authors: Yemma
authors: Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Arindam
authors: A
authors: Sen
authors: Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: Ravindra K
authors: RK
authors: Pandey
authors: Department of Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; CureFAKtor Pharmaceuticals, 14 Rockdove Lane, Orchard Park, NY 14127, USA. Electronic address: William.cance@roswellpark.org.
authors: William G
authors: WG
authors: Cance
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000187:drug effects / Q000502:physiology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D016513:Mice, SCID; D010190:Pancreatic Neoplasms; D011312:Pressure; D017434:Protein Structure, Tertiary; D047368:Tumor Burden / Q000187:drug effects; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D020533:Angiogenesis Inhibitors; D005029:Ethylenediamines; C000592901:N-((4-chlorophenyl)methyl)-N-(2-(dimethylamino)ethyl)quinolin-2-amine; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: FAK scaffold inhibition; Focal adhesion kinase; Focal adhesion targeting domain; Pancreatic cancer; Vascular endothelial growth factor receptor-3