Research Papers:

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts

Peng Hu _, Da-xiong Han, Run-sheng Ruan, Li-Mou Zheng, Shiu-Huey Chou and Chi-Meng Tzeng

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Oncotarget. 2016; 7:35741-35752. https://doi.org/10.18632/oncotarget.7140

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Peng Hu1,2, Da-xiong Han1, Run-sheng Ruan1,2, Li-Mou Zheng1, Shiu-Huey Chou3, Chi-Meng Tzeng1,2

1Translational Medicine Research Center, School of Pharmaceutical Science, Xiamen University, Xiamen, P.R. China

2Key Laboratory for Cancer T-Cell Theranostics and Clinical Translation (CTCTCT), Xiamen P.R. China

3Department of Life Science, Fu-Jen Catholic University, Xinzhuang District, New Taipei City, Taiwan

Correspondence to:

Chi-Meng Tzeng, email: [email protected]

Shiu-Huey Chou, email: [email protected]

Keywords: epidermal growth factor receptor (EGFR), tyrosine kinase inhibitors (TKIs), anilinoquinazoline, irreversible, transtinib

Received: October 07, 2015     Accepted: January 23, 2016     Published: February 02, 2016


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.

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