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Characterization of a highly selective inhibitor of the Aurora kinases |
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| Authors: | Fleur M Ferguson Zainab M Doctor Apirat Chaikuad Taebo Sim Nam Doo Kim Stefan Knapp Nathanael S Gray |
| Institution: | 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA;2. Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom;3. German Cancer Consortium (DKTK), Frankfurt site, Germany;4. Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany;5. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Republic of Korea;6. KU-KIST Graduate School of Converging Science and Technology, Korea University, Republic of Korea;7. Daegu-Gyeongbuk Medical Innovation Foundation, Republic of Korea |
| Abstract: | Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity. |
| Keywords: | PLK4 Polo-like kinase 4 FACS fluorescence activated cell sorting DMSO dimethylsulfoxide AML acute myeloid leukemia T-ALL T-cell acute lymphoblastic leukemia ABL1 Abelson Tyrosine-Protein Kinase 1 LRRK2 Leucine Rich Repeat Kinase 2 BRD4 Bromodomain-Containing Protein 4 ERK5 Mitogen-activated protein kinase 7 LC-MS/MS Liquid Chromatography–Mass Spectrometry/Mass Spectrometry Aurora kinase Selective kinase inhibitor Pan-Aurora inhibitor Mitosis Cancer |
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