Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity

被引：17

作者：

Fang, Yanfen ^{[1
]}

Kong, Yannan ^{[1
]}

Xi, Jianbei ^{[1
]}

Zhu, Mengli ^{[1
]}

Zhu, Tong ^{[1
]}

Jiang, Tongtong ^{[1
]}

Hu, Wenhao ^{[1
]}

Ma, Mingliang ^{[1
]}

Zhang, Xiongwen ^{[1
]}

机构：

[1] East China Normal Univ, Coll Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai, Peoples R China

来源：

ONCOTARGET | 2016年 / 7卷 / 48期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

NEK2; mitosis; chromosome misalignment; cytokinesis failure; apoptosis; SPINDLE ASSEMBLY CHECKPOINT; CELL-CYCLE REGULATION; BREAST-CANCER; CENTROSOME DISJUNCTION; PROTEIN-KINASES; POOR-PROGNOSIS; PHOSPHORYLATION; OVEREXPRESSION; PROGRESSION; SURVIVAL;

D O I：

10.18632/oncotarget.12687

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

NEK2 is a conserved mitotic regulator critical for cell cycle progression. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. In the present study, we have identified a novel compound MBM-5, which was found to bind to NEK2 with high affinity by docking simulations study. MBM-5 potently inhibited NEK2 kinase activity in vitro in a concentration-dependent manner. MBM-5 also suppressed cellular NEK2 kinase activity, as evidenced by the decreased phosphorylation of its substrate Hec1 on S165 in a concentration-and time-dependent manner. This inhibition impeded mitotic progression by inducing chromosome segregation defects and cytokinesis failure; therefore leading to accumulation of cells with >= 4N DNA content, which finally underwent apoptosis. More importantly, MBM-5 treatment effectively suppressed the tumor growth of human gastric and colorectal cancer cells xenografts. Taken together, we demonstrated that MBM-5 effectively inhibited the kinase activity of NEK2 and showed a potential application in anti-cancer treatment regimens.

引用

页码：79313 / 79327

页数：15

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