A Small Molecule Inhibitor, 1,2,4,5-Benzenetetraamine Tetrahydrochloride, Targeting the Y397 Site of Focal Adhesion Kinase Decreases Tumor Growth

• Published in: Journal of medicinal chemistry Vol. 51; no. 23; pp. 7405 - 7416
• Main Authors: Golubovskaya, Vita M, Nyberg, Carl, Zheng, Min, Kweh, Frederick, Magis, Andrew, Ostrov, David, Cance, William G
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 11-12-2008
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Antineoplastic agents; Apoptosis - drug effects; Binding Sites; Biological and medical sciences; Cell Adhesion - drug effects; Cell Proliferation - drug effects; Computational Biology; Computer Simulation; Computer-Aided Design; Databases, Factual; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Female; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - metabolism; General aspects; Humans; Medical sciences; Mice; Mice, Nude; Models, Molecular; Molecular Weight; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Time Factors; Antineoplastic agent; Targeting; Modeling; Dose activity relation; Structure activity relation; Hydrochlorides; Molecular model; Mammary gland; Small molecule; Mechanism of action; Tumor cell; Human; Enzyme; Transferases; Rodentia; Time response relation; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; Inhibitor; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800483v

Focal adhesion kinase (FAK) is a nonreceptor kinase that is overexpressed in many types of tumors. We developed a novel cancer-therapy approach, targeting the main autophosphorylation site of FAK, Y397, by computer modeling and screening of the National Cancer Institute (NCI) small molecule compounds database. More than 140 000 small molecule compounds were docked into the N-terminal domain of the FAK crystal structure in 100 different orientations that identified 35 compounds. One compound, 14 (1,2,4,5-benzenetetraamine tetrahydrochloride), significantly decreased viability in most of the cells to the levels equal to or higher than control FAK inhibitor 1a (2-[5-chloro-2-[2-methoxy-4-(4-morpholinyl)phenylamino]pyrimidin-4-ylamino]-N-methylbenzamide, TAE226) from Novartis, Inc. Compound 14 specifically and directly blocked phosphorylation of Y397-FAK in a dose- and time-dependent manner. It increased cell detachment and inhibited cell adhesion in a dose-dependent manner. Furthermore, 14 effectively caused breast tumor regression in vivo. Thus, targeting the Y397 site of FAK with 14 inhibitor can be effectively used in cancer therapy.