title: A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1(3,7)]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo.
abstract: Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in most solid types of tumors and plays an important role in the survival signaling. Recently, we have developed a novel computer modeling combined with a functional assay approach to target the main autophosphorylation site of FAK (Y397). Using these approaches, we identified 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1(3,7)]decane; bromide, called Y11, a small molecule inhibitor targeting Y397 site of FAK. Y11 significantly and specifically decreased FAK autophosphorylation, directly bound to the N-terminal domain of FAK. In addition, Y11 decreased Y397-FAK autophosphorylation, inhibited viability and clonogenicity of colon SW620 and breast BT474 cancer cells and increased detachment and apoptosis in vitro. Moreover, Y11 significantly decreased tumor growth in the colon cancer cell mouse xenograft model. Finally, tumors from the Y11-treated mice demonstrated decreased Y397-FAK autophosphorylation and activation of poly (ADP ribose) polymerase and caspase-3. Thus, targeting the major autophosphorylation site of FAK with Y11 inhibitor is critical for development of cancer therapeutics and carcinogenesis field.
authors.affiliation: Department of Surgical Oncology, Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. vita.golubovskaya@roswellpark.org
authors.forename: Vita M
authors.initials: VM
authors.lastname: Golubovskaya
authors.forename: Sheila
authors.initials: S
authors.lastname: Figel
authors.forename: Baotran T
authors.initials: BT
authors.lastname: Ho
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Johnson
authors.forename: Michael
authors.initials: M
authors.lastname: Yemma
authors.forename: Grace
authors.initials: G
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Carl
authors.initials: C
authors.lastname: Nyberg
authors.forename: Andrew
authors.initials: A
authors.lastname: Magis
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006572:Heterocyclic Compounds, Bridged-Ring / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: C574188:1-(2-hydroxyethyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1(3,7))decane bromide; D006572:Heterocyclic Compounds, Bridged-Ring; D047428:Protein Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D053148:Caspase 3