PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer.
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.
Carpinelli
Patrizia
P
Nerviano Medical Sciences S.r.l.-Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
Ceruti
Roberta
R
Giorgini
Maria Laura
ML
Cappella
Paolo
P
Gianellini
Laura
L
Croci
Valter
V
Degrassi
Anna
A
Texido
Gemma
G
Rocchetti
Maurizio
M
Vianello
Paola
P
Rusconi
Luisa
L
Storici
Paola
P
Zugnoni
Paola
P
Arrigoni
Claudio
C
Soncini
Chiara
C
Alli
Cristina
C
Patton
Veronica
V
Marsiglio
Aurelio
A
Ballinari
Dario
D
Pesenti
Enrico
E
Fancelli
Daniele
D
Moll
Jürgen
J
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
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