Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 23, Pages 7405-7416Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm800483v
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Funding
- NIH [CA65910]
- [BCTR0707148]
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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 la (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 ill 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.
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