LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells

Jian Zhang; Jian Wang; Qiqiang Guo; Yu Wang; Ying Zhou; Huizhi Peng; Maosheng Cheng; Dongmei Zhao; Feng Li

doi:10.1016/j.canlet.2011.11.007

LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells

Cancer Lett. 2012 Apr 1;317(1):24-32. doi: 10.1016/j.canlet.2011.11.007. Epub 2011 Nov 13.

Authors

Jian Zhang¹, Jian Wang, Qiqiang Guo, Yu Wang, Ying Zhou, Huizhi Peng, Maosheng Cheng, Dongmei Zhao, Feng Li

Affiliation

¹ 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.

PMID: 22085492
DOI: 10.1016/j.canlet.2011.11.007

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Depolymerizing Factors / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects*
Cell Proliferation / drug effects*
Cyclin D1 / metabolism
Dose-Response Relationship, Drug
ErbB Receptors / metabolism
Humans
Lim Kinases / metabolism
MAP Kinase Kinase 1 / metabolism
Matrix Metalloproteinase 2 / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Models, Molecular
Molecular Structure
Neoplasm Invasiveness
Protein Conformation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins pp60(c-src) / metabolism
Pseudopodia / drug effects
Pseudopodia / enzymology
Quinazolines / chemistry
Quinazolines / pharmacology*
Signal Transduction / drug effects
Stomach Neoplasms / enzymology*
Stomach Neoplasms / genetics
Stomach Neoplasms / pathology
Structure-Activity Relationship
Transfection
p21-Activated Kinases / antagonists & inhibitors*
p21-Activated Kinases / chemistry
p21-Activated Kinases / genetics
p21-Activated Kinases / metabolism

Substances

Actin Depolymerizing Factors
Antineoplastic Agents
CCND1 protein, human
LCH-7749944
Protein Kinase Inhibitors
Quinazolines
Cyclin D1
PAK4 protein, human
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins pp60(c-src)
LIMK1 protein, human
Lim Kinases
p21-Activated Kinases
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase 1
MAP2K1 protein, human
MMP2 protein, human
Matrix Metalloproteinase 2