Antitumor activity of a kinesin inhibitor
Antitumor activity of a kinesin inhibitor
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DOI：
10.1158/0008-5472.can-03-3839
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发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Wood, KW
中科院分区：
文献类型：
--
作者：
Sakowicz, R;Finer, JT;Wood, KW
微管运动蛋白激酶家族的几个成员在有丝分裂纺锤体功能中发挥重要作用，是发现新型抗有丝分裂癌症治疗的潜在靶点。KSP，也被称为HsEg5，是一种激酶，在双极性有丝分裂纺锤体的形成中起重要作用，并且是通过有丝分裂进行细胞周期进程所必需的。我们发现了一种有效的KSP抑制剂CK0106023，它在几种人类肿瘤细胞系中引起有丝分裂阻滞和生长抑制。我们发现CK0106023是KSP运动域atp酶的变构抑制剂，K-1为12 nM。在检测的5种激酶中，CK0106023对KSP具有特异性。在荷瘤小鼠中，CK0106023显示出与紫杉醇相当或超过紫杉醇的抗肿瘤活性，并引起与培养细胞中产生的单极有丝分裂象相同的单极有丝分裂象。KSP在增殖的人体组织中最丰富，而在培养的有丝分裂后神经元中不存在。这些发现首次证明了靶向有丝分裂运动蛋白治疗癌症的可行性。
Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a K-1 of 12 nM. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.