PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer
PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer
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DOI：
10.1158/1535-7163.mct-07-0444
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发表时间：
2007-12-01
影响因子：
5.7
通讯作者：
Moll, Jurgen
中科院分区：
文献类型：
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作者：
Carpinelli, Patrizia;Ceruti, Roberta;Moll, Jurgen
PHA-739358是一种小分子3-氨基吡唑衍生物，对Aurora激酶具有强活性，并与一些与癌症相关的受体酪氨酸激酶具有交叉反应性。PHA-739358抑制所有Aurora激酶家族成员，并在体外和体内细胞中显示出显性Aurora B激酶抑制相关细胞表型和作用机制。用PHA-739358处理细胞后观察到p53状态依赖性核内复制，Ser（10）中组蛋白H3的磷酸化受到抑制。该化合物在不同的异种移植物以及自发和转基因动物肿瘤模型中具有显着的抗肿瘤活性，并显示出良好的药代动力学和安全性特征。通过组蛋白H3磷酸化的抑制评估观察到体内靶向调节，组蛋白H3已在临床前被验证为临床阶段的候选生物标志物。使用药代动力学/药效学建模来定义药物效力，并支持活性临床剂量和方案的预测。我们的结论是，PHA-739358，这是目前在临床试验中进行测试，具有很大的治疗潜力，在抗癌治疗在广泛的癌症。
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.