FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate the cytoskeleton and act as a scaffolding and signaling protein for other adhesion molecules. The expression of FAK and its phosphorylation status show a strong correlation with the invasive phenotype of aggressive human tumors. GSK2256098 is a selective FAK inhibitor with Ki value of 0.4nM. Cellular study showed that GSK2256098 inhibited p-FAK with IC50 values ranging in 2-15nM while only showed effective on cell growth inhibition in cell lines in anchorage-independent conditions with soft agar or methylcellulose, but not in standard conditions on tissue culture plastic in tested[1]. Another study showed that GSK2256098 could dose-dependently inhibit FAK activity on its phosphorylation site with different potency according to different PDAC cells, most potent to L3.6P1 and least potent to PANC-1 cells, at concentration ranging in 0.1-10μM, as well as promote apoptosis in L3.6P1 cells through caspase-9/PARP, but showed inhibition of cell growth only in anchorage-independent manner. In vitro wound healing assays showed that pre-treatment with GSK2256098 at concentration ranging in 1-25μM for 48h caused impairment of cell motility dose-dependently in L3.6P1 and PANC-1 cells[2]. Oral administration of GSK2256098 caused dose-dependent reduction of pFAK with maximal reduction corresponding to the Cmax of GSK2256098 in mice bearing subcutaneous human tumors, suggesting the good pharmacodynamics of GSK2256098[1].
作用机制
GSK2256098 is an ATP competitive inhibitor which can bound in the ATP binding pocket of FAK.[1]
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