P21-activated kinase 4 (PAK4) is a serine/threonine protein kinase and has related to the regulation of cytoskeleton recombine, cell proliferation, gene transcription, carcinogenic transformation, cell invasion. Moreover, PAK4 overexpression, mutations, genetic amplification were detected in a variety of human tumors, making it a potential therapeutic target. Specifically, The p21-activated kinases (PAKs) are a family of serine/threonine protein kinases that act as effectors for Rac and Cdc42. Besides, PAK4 is the most extensive and in-depth member among the group II PAKs. Furthermore, Overexpression of PAK4 is in a variety of cancer cell lines, including prostate, breast, gall bladder and stomach and also in several primary tumors. Meanwhile, the important functions of PAK4 provide a theoretical basis for the discovery of PAK4 inhibitors as anticancer drugs. LCH-7749944 (GNF-PF-2356) is a potent PAK4 inhibitor and effectively suppresses the proliferation of human gastric cancer cells and induces apoptosis.
LCH-7749944 (GNF-PF-2356) is a potent PAK4 inhibitor with an IC50 of 14.93 μM. Nonetheless, LCH-7749944 effectively suppresses the proliferation of human gastric cancer cells through the downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway and induces apoptosis. Interestingly, LCH-7749944 also inhibited the formation of filopodia and induced cell elongation in SGC7901 cells. LCH-7749944 dramatically decreases levels of phospho-c-Src, phosphoPAK4, phospho-EGFR and cyclin D1 protein expression in a dose-dependent manner. LCH-7749944 prominently induces a dose-dependent increase in the percentage of cells in G1 phase and decrease in S phase. Importantly, LCH-7749944 caused successful inhibition of EGFR activity due to its inhibitory effect on PAK4. All in all, LCH-7749944 is a potent PAK4 inhibitor and effectively suppresses the proliferation of human gastric cancer cells and induces apoptosis.
References:
Zhang J, et al. Cancer Lett. 2012 Apr 1;317(1):24-32.