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]
Detect FAK expression levels and select the concentration with the most significant reduction in FAK protein expression for subsequent experiments
Int J Biol Sci. 2022 Jul 25;18(13):4932-4949.
Ishikawa cells
0.01-10 µM
24 hours
To test the sensitivity of Ishikawa and Hec1A cells to GSK2256098, Ishikawa cells were more sensitive to GSK2256098 than Hec1A cells.
Mol Cancer Ther. 2015 Jun;14(6):1466-1475.
Hec1A cells
0.01-10 µM
24 hours
To test the sensitivity of Ishikawa and Hec1A cells to GSK2256098, Ishikawa cells were more sensitive to GSK2256098 than Hec1A cells.
Mol Cancer Ther. 2015 Jun;14(6):1466-1475.
GSK2256098 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Uterine cancer model
Oral
75 mg/kg
Daily for 4-6 weeks
In the Ishikawa model, tumor growth was inhibited to a greater extent in the GSK2256098 monotherapy group compared to the Hec1A model. GSK2256098 combined with paclitaxel further reduced tumor growth and the number of tumor nodules.
搜索
