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

doi:10.3389/fchem.2021.789030

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.

Highlights

It is estimated that 2.09 million new cases of lung cancer (11.6% of the total cases) were diagnosed and 1.76 million deaths were caused by lung cancer (18.4% of the total cancer deaths) globally in 2018 (Bray et al, 2018)
The results showed that e4 and e12 suppressed the phosphorylation of Epidermal growth factor receptor (EGFR) and AKT in both PC-9 and H460 cells, especially at a concentration of 10 μM, consistent with their potent antiproliferation activities in non-small-cell lung cancer (NSCLC) cells (Figure 5)
Several of the Erlotinib derivatives showed more robust inhibitory activity against NSCLC cells including H460, H1975 and A549, compared with Erlotinib. We confirmed that these Erlotinib derivatives hah slightly lower but still adequate EGFR tyrosine kinase inhibitory activity when compared with that of Erlotinib

Summary

Introduction

It is estimated that 2.09 million new cases of lung cancer (11.6% of the total cases) were diagnosed and 1.76 million deaths were caused by lung cancer (18.4% of the total cancer deaths) globally in 2018 (Bray et al, 2018). Activating mutations in the ATP binding pocket of EGFR and excessive activation of the EGFR signaling pathway are observed in approximately 15–20% of NSCLC patients (Lynch et al, 2004; Paez et al, 2004), and many EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed as the first-line therapy for NSCLC, including the first- and second-generation EGFR- TKIs Gefitinib (Figure 1A) (Muhsin et al, 2003), Erlotinib (Figure 1B) (Schettino et al, 2008) and Afatinib (Figure 1C) (Dungo and Keating, 2013), and the thirdgeneration EGFR-TKI Osimertinib (Figure 1D) (Cross et al, 2014). Osimertinib is the only inhibitor approved to target the T790M mutation, most third-generation EGFR-TKIs designed to overcome T790M resistance have not shown themselves superior to Osimertinib with respect to antitumor efficacy. It is necessary to identify more competent agents against NSCLC that could work quickly and effectively

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Conclusion