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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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
Volume5
DOIs
Publication statusPublished - Jun 16 2015
Externally publishedYes

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Protein-Tyrosine Kinases
Phosphotransferases
Drug Resistance
Biological Phenomena
Pharmaceutical Preparations
Protein Kinases
Neoplasms
Breast Neoplasms
rosmarinic acid

ASJC Scopus subject areas

  • General

Cite this

Hsu, K. C., Sung, T. Y., Lin, C. T., Chiu, Y. Y., Hsu, J. T. A., Hung, H. C., ... Yang, J. M. (2015). Anchor-based classification and type-C inhibitors for tyrosine kinases. Scientific Reports, 5, [10938]. https://doi.org/10.1038/srep10938

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

In: Scientific Reports, Vol. 5, 10938, 16.06.2015.

Research output: Contribution to journalArticle

Hsu, KC, Sung, TY, Lin, CT, Chiu, YY, Hsu, JTA, Hung, HC, Sun, CM, Barve, I, Chen, WL, Huang, WC, Huang, CT, Chen, CH & Yang, JM 2015, 'Anchor-based classification and type-C inhibitors for tyrosine kinases', Scientific Reports, vol. 5, 10938. https://doi.org/10.1038/srep10938
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. / Anchor-based classification and type-C inhibitors for tyrosine kinases. In: Scientific Reports. 2015 ; Vol. 5.
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