High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors |
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Authors: | Miduturu Chandrasekhar V Deng Xianming Kwiatkowski Nicholas Yang Wannian Brault Laurent Filippakopoulos Panagis Chung Eunah Yang Qingkai Schwaller Juerg Knapp Stefan King Randall W Lee Jiing-Dwan Herrgard Sanna Zarrinkar Patrick Gray Nathanael S |
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Institution: | Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. |
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Abstract: | Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors. |
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