A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity
A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity
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DOI：
10.1371/journal.pone.0144675
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发表时间：
2015-12-09
期刊：
影响因子：
3.7
通讯作者：
Okaniwa, Masanori
中科院分区：
文献类型：
--
作者：
Ohashi, Akihiro;Ohori, Momoko;Okaniwa, Masanori
着丝粒相关蛋白E（CENP-E）在有丝分裂过程中调节染色体聚集和纺锤体组装检查点（SAC）。CENP-E功能的丧失导致染色体错位，导致SAC激活和细胞凋亡，在长期的有丝分裂停滞。在这里，我们描述了一种新的CENP-E的小分子抑制剂，化合物-A（Cmpd-A）的生物学和抗增殖活性。Cmpd-A抑制CENP-E运动域的ATP酶活性，作为具有ATP竞争性样行为的时间依赖性抑制剂起作用。Cmpd-A引起中期板上的染色体错配，导致延长的有丝分裂停滞。用Cmpd-A处理在多种癌细胞系中诱导抗增殖。此外，Cmpd-A在裸鼠异种移植模型中表现出抗肿瘤活性，并且该抗肿瘤活性伴随着肿瘤中磷酸组蛋白H3水平的升高。这些发现证明了CENP-E抑制剂Cmpd-A的效力及其作为抗癌治疗剂的潜力。
Centromere-associated protein E (CENP-E) regulates both chromosome congression and the spindle assembly checkpoint (SAC) during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A). Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent.