High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors

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• 作者：Chandrasekhar  ; V. Miduturu¹ ; ⁸ ; ⁹ ; Xianming Deng¹ ; ⁸ ; Nicholas Kwiatkowski¹ ; Wannian Yang² ; Laurent Brault³ ; Panagis Filippakopoulos⁴ ; Eunah Chung⁵ ; Qingkai Yang⁶ ; Juerg Schwaller³ ; Stefan Knapp⁴ ; Randall  ; W. King⁵ ; Jiing-Dwan Lee⁶ ; Sanna Herrgard⁷ ; Patrick Zarrinkar⁷ ; ⁹ ; Nathanael  ; S. Gray¹ ; ^{Nathanael_Gray@dfci.harvard.edu"" rel=""nofollow}
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：29 July 2011
• 年：2011
• 卷：18
• 期：7
• 页码：868-879
• 全文大小：1296 K

文摘

Summary

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.