title: PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer.
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 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.
authors: Nerviano Medical Sciences S.r.l.-Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors: Patrizia
authors: P
authors: Carpinelli
authors: Roberta
authors: R
authors: Ceruti
authors: Maria Laura
authors: ML
authors: Giorgini
authors: Paolo
authors: P
authors: Cappella
authors: Laura
authors: L
authors: Gianellini
authors: Valter
authors: V
authors: Croci
authors: Anna
authors: A
authors: Degrassi
authors: Gemma
authors: G
authors: Texido
authors: Maurizio
authors: M
authors: Rocchetti
authors: Paola
authors: P
authors: Vianello
authors: Luisa
authors: L
authors: Rusconi
authors: Paola
authors: P
authors: Storici
authors: Paola
authors: P
authors: Zugnoni
authors: Claudio
authors: C
authors: Arrigoni
authors: Chiara
authors: C
authors: Soncini
authors: Cristina
authors: C
authors: Alli
authors: Veronica
authors: V
authors: Patton
authors: Aurelio
authors: A
authors: Marsiglio
authors: Dario
authors: D
authors: Ballinari
authors: Enrico
authors: E
authors: Pesenti
authors: Daniele
authors: D
authors: Fancelli
authors: Jürgen
authors: J
authors: Moll
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D011720:Pyrazoles; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib