Anchor-based classification and type-C inhibitors for tyrosine kinases

Kai Cheng Hsu, Tzu Ying Sung, Chih Ta Lin, Yi Yuan Chiu, John T A Hsu, Hui Chen Hung, Chung Ming Sun, Indrajeet Barve, Wen Liang Chen, Wen Chien Huang, Chin Ting Huang, Chun Hwa Chen, Jinn Moon Yang

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7 引文 斯高帕斯(Scopus)


Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.
期刊Scientific Reports
出版狀態已發佈 - 六月 16 2015

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    Hsu, K. C., Sung, T. Y., Lin, C. T., Chiu, Y. Y., Hsu, J. T. A., Hung, H. C., Sun, C. M., Barve, I., Chen, W. L., Huang, W. C., Huang, C. T., Chen, C. H., & Yang, J. M. (2015). Anchor-based classification and type-C inhibitors for tyrosine kinases. Scientific Reports, 5, [10938].