PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity.
OBJECTIVE
Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy.


METHODS
The activity of PHA-680632 was assayed in a biochemical ATP competitive kinase assay. A wide panel of cell lines was evaluated for antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation. Specific knockdown of the targets by small interfering RNA was followed to validate the observed phenotypes. Efficacy was determined in different xenograft models and in a transgenic animal model of breast cancer.


RESULTS
PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. Histone H3 phosphorylation in Ser10 is mediated by Aurora B kinase, and our kinetic studies on its inhibition by PHA-680632 in vitro and in vivo show that phosphorylation of histone H3 is a good biomarker to follow activity of PHA-680632.


CONCLUSIONS
PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic. On treatment, different cell lines respond differentially, suggesting the absence of critical cell cycle checkpoints that could be the basis for a favorable therapeutic window.
Soncini
Chiara
C
Nerviano Medical Sciences S.r.l.-Oncology, Milan, Italy.
Carpinelli
Patrizia
P
Gianellini
Laura
L
Fancelli
Daniele
D
Vianello
Paola
P
Rusconi
Luisa
L
Storici
Paola
P
Zugnoni
Paola
P
Pesenti
Enrico
E
Croci
Valter
V
Ceruti
Roberta
R
Giorgini
Maria Laura
ML
Cappella
Paolo
P
Ballinari
Dario
D
Sola
Francesco
F
Varasi
Mario
M
Bravo
Rodrigo
R
Moll
Jürgen
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D064107:Aurora Kinase B; D064127:Aurora Kinases; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C524543:PHA 680632; D011720:Pyrazoles; D011758:Pyrroles; D011994:Recombinant Proteins; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases