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Journal of Cancer Research and Clinical Oncology

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01-01-2010 | Original Paper

Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen

Authors: John McLaughlin, Vadim Markovtsov, Hui Li, Steve Wong, Marina Gelman, Yanhong Zhu, Christian Franci, D. Wayne Lang, Erlina Pali, Joe Lasaga, Caroline Low, Feifei Zhao, Betty Chang, Tarikere L. Gururaja, Weiduan Xu, Muhammad Baluom, David Sweeny, David Carroll, Arvinder Sran, Sambaiah Thota, Manjeet Parmer, Angela Romane, George Clemens, Elliott Grossbard, Kunbin Qu, Yonchu Jenkins, Taisei Kinoshita, Vanessa Taylor, Sacha J. Holland, Ankush Argade, Rajinder Singh, Polly Pine, Donald G. Payan, Yasumichi Hitoshi

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2010

Abstract

Purpose

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 The endoreduplication cycle induced by R763/AS703569 was irreversible even after the compound was withdrawn from the culture.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.

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Title: Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen
Authors: John McLaughlin
Vadim Markovtsov
Hui Li
Steve Wong
Marina Gelman
Yanhong Zhu
Christian Franci
D. Wayne Lang
Erlina Pali
Joe Lasaga
Caroline Low
Feifei Zhao
Betty Chang
Tarikere L. Gururaja
Weiduan Xu
Muhammad Baluom
David Sweeny
David Carroll
Arvinder Sran
Sambaiah Thota
Manjeet Parmer
Angela Romane
George Clemens
Elliott Grossbard
Kunbin Qu
Yonchu Jenkins
Taisei Kinoshita
Vanessa Taylor
Sacha J. Holland
Ankush Argade
Rajinder Singh
Polly Pine
Donald G. Payan
Yasumichi Hitoshi
Publication date: 01-01-2010
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2010
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-009-0641-1

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