Carpinelli Patrizia, Ceruti Roberta, Giorgini Maria Laura, Cappella Paolo, Gianellini Laura, Croci Valter, Degrassi Anna, Texido Gemma, Rocchetti Maurizio, Vianello Paola, Rusconi Luisa, Storici Paola, Zugnoni Paola, Arrigoni Claudio, Soncini Chiara, Alli Cristina, Patton Veronica, Marsiglio Aurelio, Ballinari Dario, Pesenti Enrico, Fancelli Daniele, Moll Jürgen
Nerviano Medical Sciences S.r.l.-Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68. doi: 10.1158/1535-7163.MCT-07-0444.
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.
PHA - 739358是一种小分子3 - 氨基吡唑衍生物，对极光激酶具有强大活性，并与一些与癌症相关的受体酪氨酸激酶存在交叉反应。PHA - 739358抑制所有极光激酶家族成员，并在体外和体内细胞中显示出与极光B激酶抑制相关的显性细胞表型和作用机制。在用PHA - 739358处理细胞后，观察到p53状态依赖性核内复制，并且组蛋白H3的Ser(10)位点磷酸化受到抑制。该化合物在不同的异种移植瘤以及自发和转基因动物肿瘤模型中具有显著的抗肿瘤活性，并显示出良好的药代动力学和安全性特征。通过抑制组蛋白H3的磷酸化评估观察到体内靶点调节，组蛋白H3磷酸化已在临床前被验证为临床阶段的候选生物标志物。药代动力学/药效学建模用于确定药物效力，并支持对活性临床剂量和给药方案的预测。我们得出结论，目前正在临床试验中进行测试的PHA - 739358在广泛的癌症抗癌治疗中具有巨大的治疗潜力。
