Erasmus University Medical Center, Daniel den Hoed Cancer Center, Department of Medical Oncology, Groene Hilledijk 301, Rotterdam, the Netherlands.
Expert Opin Investig Drugs. 2012 Mar;21(3):383-93. doi: 10.1517/13543784.2012.652303. Epub 2012 Jan 13.
Drugs that interfere with the normal progression of mitosis belong to the most successful cytotoxic agents currently used for anticancer treatment. Aurora kinases are serine/threonine kinases that function as key regulators of mitosis and are frequently overexpressed in human cancers. The use of several small molecule aurora kinase inhibitors as potential anticancer therapeutic is being investigated. Danusertib (formerly PHA-739358) is a small ATP competitive molecule that inhibits aurora A, B and C kinases. Interestingly, danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. These tyrosine kinases are involved in the pathogenesis of a variety of malignancies and the observed multi-target inhibition may increase the antitumor activity resulting in extending the indication. Danusertib was one of the first aurora kinase inhibitors to enter the clinic and has been studied in Phase I and II trials.
This review provides an updated summary of preclinical and clinical experience with danusertib up to July 2011.
Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors.
干扰有丝分裂正常进程的药物属于目前用于癌症治疗的最成功的细胞毒性药物。极光激酶是丝氨酸/苏氨酸激酶，作为有丝分裂的关键调节因子，在人类癌症中经常过度表达。目前正在研究几种小分子极光激酶抑制剂作为潜在的抗癌治疗药物。Danusertib（以前称为 PHA-739358）是一种小分子 ATP 竞争抑制剂，可抑制极光 A、B 和 C 激酶。有趣的是，danusertib 还抑制几种受体酪氨酸激酶，如 Abl、Ret、FGFR-1 和 TrkA。这些酪氨酸激酶参与多种恶性肿瘤的发病机制，观察到的多靶点抑制可能会增加抗肿瘤活性，从而扩大适应证。Danusertib 是最早进入临床的极光激酶抑制剂之一，已在 I 期和 II 期临床试验中进行了研究。
本综述提供了截至 2011 年 7 月 danusertib 的临床前和临床经验的最新总结。
未来的 danusertib 研究应侧重于将该药物与其他靶向抗癌药物、化疗或放疗联合应用的可能性。作为单一药物，danusertib 可能在治疗白血病方面比治疗实体瘤更有前景。
