1. Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.
- Author
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Hu P, Han DX, Ruan RS, Zheng LM, Chou SH, and Tzeng CM
- Subjects
- Acrylamides chemical synthesis, Acrylamides pharmacology, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors genetics, Erlotinib Hydrochloride pharmacology, Erlotinib Hydrochloride therapeutic use, Female, Gefitinib, Humans, Inhibitory Concentration 50, Lung Neoplasms genetics, Mice, Mice, Nude, Molecular Docking Simulation, Mutation, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Quinazolines chemical synthesis, Quinazolines pharmacology, Xenograft Model Antitumor Assays, Acrylamides therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors antagonists & inhibitors, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Quinazolines therapeutic use
- Abstract
Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are derived from the anilinoquinazoline scaffold. Guided by molecular modeling, this series of analogs was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and to achieve high levels of anti-tumor activity in cell cultures and in xenografts. The most promising compound 13c ((E) -N - (4 - (4 - (3-fluorobenzyloxy) -3- chlorophenylamino) -7-ethoxyquinazolin-6-yl) -3- ((S) -pyrrolidin-2-yl)acrylamide, which we named Transtinib) displayed strong anti-proliferative activity against the H1975 and A431 cell lines with IC50 values of 34 nM and 62 nM, respectively. In xenograft models, Transtinib significantly decreases tumor size for a prolonged period of time. These results suggest that Transtinib is a potential cancer therapeutic drug lead for the inhibition of mutant EGFR to overcome the development of resistance., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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