Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen.
OBJECTIVE
Aurora kinases play a key role in mitotic progression. Over-expression of Aurora kinases is found in several human cancers and correlated with histological malignancy and clinical outcomes. Therefore, Aurora kinase inhibitors should be useful in the treatment of cancers.


METHODS
Cell-based screening methods have an advantage over biochemical approaches because hits can be optimized to inhibit targets in the proper intracellular context. We developed a novel Aurora kinase inhibitor R763/AS703569 using an image-based phenotypic screen. The anti-proliferative effect was examined in a panel of tumor cell lines and primary cells. The efficacy was determined in a broad panel of xenograft models.


RESULTS
R763/AS703569 inhibits Aurora kinases, along with a limited number of other kinases including FMS-related tyrosine kinase 3 (FLT3), and has potent anti-proliferative activity against many cell types accompanying unique phenotypic changes such as enlarged cell size, endoreduplication and apoptosis. The endoreduplication cycle induced by R763/AS703569 was irreversible even after the compound was withdrawn from the culture. Oral administration of R763/AS703569 demonstrated marked inhibition of tumor growth in xenograft models of pancreatic, breast, colon, ovarian, and lung tumors and leukemia. An acute myeloid leukemia cell line MV4-11, which carries a FLT3 internal tandem duplication mutation, is particularly sensitive to R763/AS703569 in vivo.


CONCLUSIONS
R763/AS703569 is a potent inhibitor of Aurora kinases and exhibited significant anti-proliferative activity against a wide range of tumor cells both in vitro and in vivo. Inhibition of Aurora kinases has the potential to be a new addition to the treatment of cancers.
McLaughlin
John
J
Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
Markovtsov
Vadim
V
Li
Hui
H
Wong
Steve
S
Gelman
Marina
M
Zhu
Yanhong
Y
Franci
Christian
C
Lang
D  Wayne
D
Pali
Erlina
E
Lasaga
Joe
J
Low
Caroline
C
Zhao
Feifei
F
Chang
Betty
B
Gururaja
Tarikere L
TL
Xu
Weiduan
W
Baluom
Muhammad
M
Sweeny
David
D
Carroll
David
D
Sran
Arvinder
A
Thota
Sambaiah
S
Parmer
Manjeet
M
Romane
Angela
A
Clemens
George
G
Grossbard
Elliott
E
Qu
Kunbin
K
Jenkins
Yonchu
Y
Kinoshita
Taisei
T
Taylor
Vanessa
V
Holland
Sacha J
SJ
Argade
Ankush
A
Singh
Rajinder
R
Pine
Polly
P
Payan
Donald G
DG
Hitoshi
Yasumichi
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence / Q000379:methods*; D009636:Norbornanes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
C000592140:MSC1992371A; D009636:Norbornanes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases