title: Anchor-based classification and type-C inhibitors for tyrosine kinases.
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.
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Kai-Cheng
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Sung
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chih-Ta
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Chiu
authors.affiliation: 1] Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan [2] Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Sun
authors.affiliation: Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Indrajeet
authors.initials: I
authors.lastname: Barve
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei City, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Chin-Ting
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 1] Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan [2] Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Jinn-Moon
authors.initials: JM
authors.lastname: Yang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D015195:Drug Design; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase