This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Carpinelli, P. Articles by Moll, J. Search for Related Content PubMed PubMed Citation Articles by Carpinelli, P. Articles by Moll, J.

Research Articles: Therapeutics, Targets, and Development

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

Nerviano Medical Sciences S.r.l.—Oncology, Nerviano, Milan, Italy

Requests for reprints: Jürgen Moll, Nerviano Medical Sciences S.r.l.—Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy. Phone: 39-331-58-1396; Fax: 39-331-58-1374. E-mail: jurgen.moll{at}nervianoms.com

Abstract

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 Ser¹⁰ 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. [Mol Cancer Ther 2007;6(12):3158–68]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/ 2/07; revised 10/ 3/07; accepted 11/ 1/07.