A small molecule inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the y397 site of focal adhesion kinase decreases tumor growth.
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.
Golubovskaya
Vita M
VM
Department of Surgery, UF Shands Cancer Center, Department of Pathology and Laboratory Medicine,University of Florida, Gainesville, Florida 32610-0245, USA.
Nyberg
Carl
C
Zheng
Min
M
Kweh
Frederick
F
Magis
Andrew
A
Ostrov
David
D
Cance
William G
WG
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D003198:Computer Simulation; D017076:Computer-Aided Design; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases