title: Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.
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.
authors: Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China.|Key Laboratory for Cancer T-Cell Theranostics and Clinical Translation (CTCTCT), Xiamen, P.R. China.
authors: Peng
authors: P
authors: Hu
authors: Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China.
authors: Da-Xiong
authors: DX
authors: Han
authors: Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China.|Key Laboratory for Cancer T-Cell Theranostics and Clinical Translation (CTCTCT), Xiamen, P.R. China.
authors: Run-Sheng
authors: RS
authors: Ruan
authors: Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China.
authors: Li-Mou
authors: LM
authors: Zheng
authors: Department of Life Science, Fu-Jen Catholic University, Xinzhuang District, New Taipei City, Taiwan.
authors: Shiu-Huey
authors: SH
authors: Chou
authors: Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China.|Key Laboratory for Cancer T-Cell Theranostics and Clinical Translation (CTCTCT), Xiamen, P.R. China.
authors: Chi-Meng
authors: CM
authors: Tzeng
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D000077156:Gefitinib; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000625797:transtinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: anilinoquinazoline; epidermal growth factor receptor (EGFR); irreversible; transtinib; tyrosine kinase inhibitors (TKIs)