Danusertib (formerly PHA-739358) - A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor
Danusertib (formerly PHA-739358) - A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor
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DOI：
10.1007/978-3-642-01222-8_14
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发表时间：
2010-01-01
期刊：
影响因子：
--
通讯作者：
Bruemmendorf, Tim H.
中科院分区：
文献类型：
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作者：
Gontarewicz, Artur;Bruemmendorf, Tim H.
Aurora 激酶属于高度保守的丝氨酸/苏氨酸蛋白激酶家族。它们作为关键的有丝分裂调节剂发挥着重要作用，控制着有丝分裂的进入、中心体功能、染色体组装和分离。与许多其他有丝分裂调节因子一样，极光激酶经常被发现在癌细胞中异常过度表达。因此，这些蛋白质已成为开发新抗癌疗法的有吸引力的靶标。事实上，多种Aurora激酶小分子抑制剂已经被开发出来，其中一些在I期和II期临床试验中已在多种人类肿瘤中显示出良好的临床疗效。其中，目前最先进的临床化合物之一是 Danusertib（以前称为 PHA-739358），它对所有已知的 Aurora 激酶以及其他癌症相关激酶（例如 Bcr-Abl 酪氨酸激酶，包括其多重耐药 T3151 突变体）均表现出抑制活性。在接受伊马替尼治疗的 CML 患者中，临床观察到的所有耐药性中高达 25% 是由这种突变造成的。然而，预计这种特殊突变在未来将发挥更重要的临床作用，因为除了伊马替尼之外，它还赋予对第二代 Bcr-Abl 抑制剂如尼洛替尼、达沙替尼和博舒替尼的耐药性。因此，用 Danusertib 等化合物联合 Aurora 和 Bcr-Abl 抑制（后者包括赋予高度耐药性的突变）代表了治疗 Bcr-Abl 阳性白血病（尤其是二线和三线治疗的白血病）的一种有前景的新策略。
The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T3151 mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.