A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl) -3, 5, 7-triaza-1-azoniatricyclo [3.3.1.13,7]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo

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 s...

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Published in:Carcinogenesis (New York) 2012-05, Vol.33 (5), p.1004-1013
Main Authors: GOLUBOVSKAYA, Vita M, FIGEL, Sheila, GELMAN, Irwin H, CANCE, William G, HO, Baotran T, JOHNSON, Christopher P, YEMMA, Michael, HUANG, Grace, MIN ZHENG, NYBERG, Carl, MAGIS, Andrew, OSTROV, David A
Format: Article
Language:English
Subjects:
Animal models
Animals
Apoptosis - drug effects
Biological and medical sciences
Biology, Genetics and Epigenetics
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinogenesis, carcinogens and anticarcinogens
Caspase 3 - metabolism
Cell Line, Tumor
Cell Survival - drug effects
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Female
Focal Adhesion Kinase 1 - antagonists & inhibitors
Focal Adhesion Kinase 1 - metabolism
Heterocyclic Compounds, Bridged-Ring - pharmacology
Humans
Medical sciences
Mice
Mice, Nude
Phosphorylation - drug effects
Poly(ADP-ribose) Polymerases - metabolism
Protein Kinase Inhibitors - pharmacology
Protein Structure, Tertiary - drug effects
Tumor Stem Cell Assay - methods
Tumors
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Summary: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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgs120