Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity.

• 影响指数: 4.927
• 发表时间: Feb 2018 14
• 来源期刊: Molecules
• DOI: 10.3390/molecules23020417
• PMID: 29443911
• 文章类型: Journal Article
• 中科院分区: Q3
• 作者列表: Wu T,Pang Y,Guo J,Yin W,Zhu M,Hao C,Wang K,Wang J,Zhao D,Cheng M

关键词: 2,4-diaminoquinazoline; PAK4 inhibitor; anticancer; p21-activated kinase

Mesh: A549 Cells; Cell Movement / drug effects; Cell Proliferation / drug effects; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms / drug therapy genetics; Neoplasm Invasiveness / genetics pathology; Quinazolines / chemical synthesis chemistry pharmacology; p21-Activated Kinases / antagonists & inhibitors genetics

Abstract

A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.