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^*

来源：Scientific Reports, 2015, 5(1): 10938.

DOI：10.1038/srep10938

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.

• 出版日期2015-6-16