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Updated: Jun 21, 2026
Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
Published on: July 30, 2020
Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic
John McLaughlin1, Vadim Markovtsov, Hui Li
1Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
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 The endoreduplication cycle induced by R763/AS703569 was irreversible even after the compound was withdrawn from the culture.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.
Insights
A novel Aurora kinase inhibitor, R763/AS703569, effectively reduces tumor growth in various cancers. This compound shows potent anti-proliferative effects and induces irreversible endoreduplication in cancer cells, highlighting its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aurora kinases are crucial for mitotic progression.
- Overexpression of Aurora kinases is linked to cancer malignancy and poor clinical outcomes.
- Targeting Aurora kinases offers a promising strategy for cancer therapy.
Purpose of the Study:
- To develop and characterize a novel Aurora kinase inhibitor.
- To evaluate the anti-proliferative and anti-tumor efficacy of R763/AS703569.
- To explore the therapeutic potential of Aurora kinase inhibition in cancer treatment.
Main Methods:
- A novel Aurora kinase inhibitor, R763/AS703569, was identified using an image-based phenotypic screen.
- The anti-proliferative effects were assessed in a diverse panel of tumor cell lines and primary cells.
- In vivo efficacy was determined using a broad range of tumor xenograft models.
Main Results:
- R763/AS703569 inhibits Aurora kinases and other kinases like FLT3, demonstrating potent anti-proliferative activity.
- The compound induced unique phenotypic changes, including cell enlargement, endoreduplication, and apoptosis, with irreversible endoreduplication.
- Oral administration of R763/AS703569 significantly inhibited tumor growth in xenograft models of pancreatic, breast, colon, ovarian, lung tumors, and leukemia, with notable sensitivity in FLT3-mutated AML.
Conclusions:
- R763/AS703569 is a potent Aurora kinase inhibitor with significant in vitro and in vivo anti-tumor activity.
- The compound's ability to induce irreversible endoreduplication and its efficacy across various tumor types support its therapeutic potential.
- Targeting Aurora kinases with inhibitors like R763/AS703569 represents a promising new avenue for cancer treatment.
