標題: Anchor-based classification and type-C inhibitors for tyrosine kinases
作者: Hsu, Kai-Cheng
Sung, Tzu-Ying
Lin, Chih-Ta
Chiu, Yi-Yuan
Hsu, John T. -A.
Hung, Hui-Chen
Sun, Chung-Ming
Barve, Indrajeet
Chen, Wen-Liang
Huang, Wen-Chien
Huang, Chin-Ting
Chen, Chun-Hwa
Yang, Jinn-Moon
生物科技學系
生物資訊及系統生物研究所
應用化學系
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
Department of Applied Chemistry
公開日期: 16-Jun-2015
摘要: 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.
URI: http://dx.doi.org/10.1038/srep10938
http://hdl.handle.net/11536/127889
ISSN: 2045-2322
DOI: 10.1038/srep10938
期刊: SCIENTIFIC REPORTS
Volume: 5
起始頁: 0
結束頁: 0
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