LCH-7749944 is a novel and potent p21-activated kinase 4 (PAK4) inhibitor that suppresses proliferation and invasion in human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway and causes successful inhibition of EGFR activity.
P21-activated kinase 4 (PAK4), a serine/threonine protein kinase, has involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. Moreover, PAK4 overexpression, genetic amplification and mutations were detected in a variety of human tumors, which make it potential therapeutic target. LCH-7749944 is a potent PAK4 inhibitor with an IC50 value of 14.93 μM. In MTT assay, LCH-7749944 treatment inhibited the proliferation of MKN-1, BGC823, SGC7901 and MGC803 cells in a concentration dependent manner. Further, exposure of SGC7901 cells to various concentrations of LCH-7749944 for different hours (12 h, 24 h and 48 h) prominently induced a dose-dependent increase in the percentage of cells in G1 phase and decrease in S phase compared with the control group, indicating that LCH-7749944 can arrest SGC7901 cells in the G1-S phase of the cell cycle. Furthermore, exposure of SGC7901 to LCH-7749944 (5, 10, 20 and 30 μM) for 24 h dramatically decreased levels of phospho-PAK4, phospho-c-Src, phospho-EGFR and cyclin D1 protein expression in a dose-dependent manner. Moreover, In SGC7901 and BGC823 cell lines, a dose-dependent decrease in cell migration and invasiveness was seen following treatment with LCH-7749944. Notably, LCH-7749944 inhibited PAK4-induced filopodia in a dose-dependent manner. Removal of LCH-7749944 from the culture media restored the ability of cells filopodia formation indicating that the effect of LCH-7749944 is reversible in live cells[1].
作用机制
LCH 7749944 forms hydrogen bond with Leu398 of PAK4 binding site[1].
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