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. In this paper we found that LCH-7749944, a novel and potent PAK4 inhibitor, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 significantly inhibited the migration and invasion of human gastric cancer cells in conjunction with concomitant blockage of PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 pathways. Interestingly, LCH-7749944 also inhibited the formation of filopodia and induced cell elongation in SGC7901 cells. Importantly, LCH-7749944 caused successful inhibition of EGFR activity due to its inhibitory effect on PAK4. Taken together, these results provided novel insights into the development of PAK4 inhibitor and potential therapeutic strategies for gastric cancer.

中文翻译：

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LCH-7749944是一种新型且有效的p21活化激酶4抑制剂，可抑制人胃癌细胞的增殖和侵袭。

P21激活激酶4（PAK4）是一种丝氨酸/苏氨酸蛋白激酶，参与细胞骨架重组，细胞增殖，基因转录，致癌转化和细胞侵袭的调控。此外，在多种人类肿瘤中检测到PAK4的过表达，基因扩增和突变，使其成为潜在的治疗靶标。在本文中，我们发现新型有效的PAK4抑制剂LCH-7749944可通过下调PAK4 / c-Src / EGFR / cyclin D1途径有效抑制人胃癌细胞的增殖。此外，LCH-7749944与PAK4 / LIMK1 / cofilin和PAK4 / MEK-1 / ERK1 / 2 / MMP2途径的同时阻断一起，能显着抑制人胃癌细胞的迁移和侵袭。有趣的是，LCH-7749944还抑制了丝状伪足的形成并诱导了SGC7901细胞中的细胞伸长。重要的是，LCH-7749944由于其对PAK4的抑制作用，成功地抑制了EGFR活性。综上所述，这些结果为PAK4抑制剂的开发和胃癌的潜在治疗策略提供了新颖的见解。