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

• Published in: Molecular cancer therapeutics Vol. 6; no. 12; pp. 3158 - 3168
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-12-2007
• Subjects: Abl; Animals; Aurora kinase; Aurora Kinase B; Aurora Kinases; Benzamides - pharmacokinetics; Benzamides - pharmacology; Benzamides - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Neoplasms - drug therapy; Neoplasms - enzymology; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats; Rats, Sprague-Dawley; Ret; small molecule kinase inhibitor; TrkA
• ISSN: 1535-7163; 1538-8514
• 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. [Mol Cancer Ther
2007;6(12):3158–68]