title: LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells.
abstract: 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.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Qiqiang
authors.initials: Q
authors.lastname: Guo
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Huizhi
authors.initials: H
authors.lastname: Peng
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhao
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009361:Neoplasm Invasiveness; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013329:Structure-Activity Relationship; D014162:Transfection; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C570630:LCH-7749944; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019938:Cyclin D1; C116367:PAK4 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); C515892:LIMK1 protein, human; D054461:Lim Kinases; D054462:p21-Activated Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2