ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent
ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent
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DOI：
10.1016/j.ccr.2005.02.009
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发表时间：
2005-03-01
期刊：
影响因子：
50.3
通讯作者：
Reddy, EP
中科院分区：
文献类型：
--
作者：
Gumireddy, K;Reddy, MVR;Reddy, EP
据报道，polo样激酶1 （Plk1）在许多人类肿瘤中表达升高，抑制Plk1活性导致其有丝分裂停止和凋亡。在这里，我们描述了ON01910的概况，这是一种Plk1活性的小分子抑制剂，它诱导肿瘤细胞的有丝分裂停滞，其特征是纺锤体异常导致细胞凋亡。该化合物不竞争atp，但竞争酶的底物结合位点。在体内，该化合物没有表现出血液毒性、肝损伤或神经毒性，并且在各种异种移植裸鼠模型中是肿瘤生长的有效抑制剂。ON01910与几种化疗药物表现出很强的协同作用，经常诱导肿瘤完全消退。
Elevated expression of polo-like kinasel1 (Plk1) has been reported in many human tumors, and inhibition of Plk1 activity results in their mitotic arrest and apoptosis. Here we describe the profile of ON01910, a small molecule inhibitor of Plk1 activity, which induces mitotic arrest of tumor cells characterized by spindle abnormalities leading to their apoptosis. This compound was not ATP-competitive, but competed for the substrate binding site of the enzyme. In vivo, this compound did not exhibit hematotoxicity, liver damage, or neurotoxicity, and was a potent inhibitor of tumor growth in a variety of xenograft nude mouse models. ON01910 showed strong synergy with several chemotherapeutic agents, often inducing complete regression of tumors.