PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer

被引：221

作者：

Carpinelli, Patrizia ^{[1
]}

Ceruti, Roberta ^{[1
]}

Giorgini, Maria Laura ^{[1
]}

Cappella, Paolo ^{[1
]}

Gianellini, Laura ^{[1
]}

Croci, Valter ^{[1
]}

Degrassi, Anna ^{[1
]}

Texido, Gernma ^{[1
]}

Rocchetti, Maurizio ^{[1
]}

Vianello, Paola ^{[1
]}

Rusconi, Luisa ^{[1
]}

Storici, Paola ^{[1
]}

Zugnoni, Paola ^{[1
]}

Arrigoni, Claudio ^{[1
]}

Soncini, Chiara ^{[1
]}

Alli, Cristina ^{[1
]}

Patton, Veronica ^{[1
]}

Marsiglio, Aurelio ^{[1
]}

Ballinari, Dario ^{[1
]}

Pesenti, Enrico ^{[1
]}

Fancelli, Daniele ^{[1
]}

Moll, Jurgen ^{[1
]}

机构：

[1] Nerviano Med Sci SRI Oncol, I-20014 Milan, Italy

来源：

MOLECULAR CANCER THERAPEUTICS | 2007年 / 6卷 / 12期

关键词：

D O I：

10.1158/1535-7163.MCT-07-0444

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：3158 / 3168

页数：11

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[1] Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1 [J].