Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen.
Abstract | PURPOSE: 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 The endoreduplication cycle induced by R763/ AS703569 was irreversible even after the compound was withdrawn from the culture.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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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 |
Journal | Journal of cancer research and clinical oncology
(J Cancer Res Clin Oncol)
Vol. 136
Issue 1
Pg. 99-113
(Jan 2010)
ISSN: 1432-1335 [Electronic] Germany |
PMID | 19609559
(Publication Type: Journal Article)
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Chemical References |
- MSC1992371A
- Norbornanes
- Protein Kinase Inhibitors
- Pyrimidines
- Aurora Kinases
- Protein Serine-Threonine Kinases
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Topics |
- Animals
- Apoptosis
(drug effects)
- Aurora Kinases
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
- Female
- Flow Cytometry
- HL-60 Cells
- HeLa Cells
- Humans
- Mice
- Mice, Inbred NOD
- Mice, Inbred Strains
- Mice, Nude
- Mice, SCID
- Microscopy, Fluorescence
(methods)
- Norbornanes
(pharmacology)
- Protein Kinase Inhibitors
(pharmacology)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Pyrimidines
(pharmacology)
- Survival Analysis
- Xenograft Model Antitumor Assays
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