Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer

Ge Sun; Longfei Mao; Wenjing Deng; Shuxiang Xu; Jie Zhao; Jianxue Yang; Kaitai Yao; Miaomiao Yuan; Wei Li

doi:10.3389/fchem.2021.789030

Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer

Front Chem. 2022 Jan 7:9:789030. doi: 10.3389/fchem.2021.789030. eCollection 2021.

Authors

Ge Sun¹, Longfei Mao², Wenjing Deng¹, Shuxiang Xu¹, Jie Zhao², Jianxue Yang^{3

4}, Kaitai Yao¹, Miaomiao Yuan⁵, Wei Li²

Affiliations

¹ Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
² Henan Engineering Research Center of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China.
³ Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China.
⁴ School of Nursing, Henan University of Science and Technology, Luoyang, China.
⁵ The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are emerging at the vanguard of therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the increasing therapeutic resistance caused by novel mutations or activated bypass pathways has impaired their performance. In this study, we link one of the commercial EGFR-TKIs, Erlotinib, to different azide compounds to synthesize a novel class of 1,2,3-triazole ring-containing Erlotinib derivatives. We discovered that several new compounds show robust antiproliferation activity against diverse NSCLC cells in vitro including PC-9, H460, H1975 and A549. Two of the most potent compounds, e4 and e12 have been found to be more efficient than Erlotinib in all NSCLC cell lines except PC-9. They significantly induce apoptosis and cell cycle arrest in PC-9 and H460 cells. The antitumor efficacy of compound e4 in vivo is close to that of Erlotinib in a PC-9 xenograft mouse model. Most Erlotinib-1,2,3-triazole compounds exhibit moderate to good inhibitory activities toward wild-type EGFR as indicated by enzyme-linked immunosorbent assay (ELISA), and the EGFR phosphorylation was inhibited in H460 and PC-9 cells exposed to e4 or e12. These data suggest that these Erlotinib-1,2,3-triazole compounds are suitable candidates for use against NSCLC and more unknown mechanisms merit further investigation.

Keywords: 1,2,3-triazole; EGFR; NSCLC; anti-tumor; erlotinib.