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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11 Citations (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.

Original languageEnglish
Article number10938
JournalScientific Reports
Publication statusPublished - Jun 16 2015
Externally publishedYes

ASJC Scopus subject areas

  • General


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