Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity.
Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity.
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MBM-5 通过抑制 NEK2 激酶活性在胃肠道癌症中的临床前活性
DOI：
10.18632/oncotarget.12687
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Fang Y;Kong Y;Xi J;Zhu M;Zhu T;Jiang T;Hu W;Ma M;Zhang X
NEK 2是一种保守的有丝分裂调节因子，对细胞周期进程至关重要。NEK 2的异常表达已在多种人类癌症中发现，使其成为设计新型抗癌疗法的有吸引力的分子靶标。在本研究中，我们已经确定了一个新的化合物MBM-5，它被发现与NEK 2的对接模拟研究具有高亲和力的结合。MBM-5在体外以浓度依赖性方式有效抑制NEK 2激酶活性。MBM-5还抑制细胞NEK 2激酶活性，如通过以浓度和时间依赖性方式降低其底物Hec 1在S165上的磷酸化所证明的。这种抑制通过诱导染色体分离缺陷和胞质分裂失败而阻碍有丝分裂进程;因此导致具有≥ 4 N DNA含量的细胞积聚，其最终经历凋亡。更重要的是，MBM-5治疗有效地抑制了人胃癌和结直肠癌细胞异种移植物的肿瘤生长。综上所述，我们证明MBM-5有效地抑制NEK 2的激酶活性，并在抗癌治疗方案中显示出潜在的应用。
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.