Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules.
Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules.
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DOI：
10.1158/0008-5472.can-11-2364
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Pyne NJ
中科院分区：
文献类型：
--
作者：
Pyne S;Bittman R;Pyne NJ
有相当多的证据表明，鞘氨醇激酶在癌症进展中起关键作用，这可能涉及癌细胞的正选择，这些癌细胞由于该酶的过度表达而具有存活和生长优势。因此，鞘氨醇激酶的抑制剂代表了一类具有作为抗癌剂的潜力的新型化合物。抑制剂效力差是阻碍这些化合物成功转化为临床的主要问题。然而，最近的发现表明，鞘氨醇激酶1是一种变构酶，一些抑制剂通过诱导酶的蛋白酶体降解或具有纳摩尔效力来提供改善的有效性。在此，我们提供了一个关于这些最新发展的观点，并强调了将鞘氨醇激酶的基本药理学和生化研究结果转化为治疗癌症的新药发现计划的重要性。
There is considerable evidence that sphingosine kinases play a key role in cancer progression, which might involve positive selection of cancer cells that have been provided with a survival and growth advantage as a consequence of over-expression of the enzyme. Therefore, inhibitors of sphingosine kinase represent a novel class of compounds that have potential as anti-cancer agents. Poor inhibitor potency is a major issue that has precluded successful translation of these compounds into the clinic. However, recent discoveries have shown that sphingosine kinase 1 is an allosteric enzyme and that some inhibitors offer improved effectiveness by inducing proteasomal degradation of the enzyme or having nanomolar potency. Herein, we provide a perspective about these recent developments and highlight the importance of translating basic pharmacological and biochemical findings on sphingosine kinase into new drug discovery programmes for treatment of cancer.