Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study.

• 影响指数: 3.461
• 发表时间: 07 2017 1
• 来源期刊: Bioorg Med Chem
• DOI: 10.1016/j.bmc.2017.04.047
• PMID: 28502459
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Guo J,Zhu M,Wu T,Hao C,Wang K,Yan Z,Huang W,Wang J,Zhao D,Cheng M

关键词: Indolin-2-one; Molecular docking; PAK4 inhibitor; Structure-activity relationship; p21-Activated kinase

Mesh: Antineoplastic Agents / chemical synthesis chemistry pharmacology; Cell Line, Tumor; Cell Proliferation / drug effects; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Indoles / chemical synthesis chemistry pharmacology; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors / chemical synthesis chemistry pharmacology; Structure-Activity Relationship; p21-Activated Kinases / antagonists & inhibitors metabolism

Abstract

Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50=22nM, 16nM and 27nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50=0.83μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.