J Cancer 2023; 14(1):152-162. doi:10.7150/jca.77788 This issue Cite

Research Paper

Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo

Mengzhen Lai1,2*, Tao Zhang2*, Hao Chen3*, Peiran Song2,4*, Linjiang Tong2, Jiaying Chen2,6, Yingqiang Liu2, Yi Ning2,6, Fang Feng2, Yan Li2, Haotian Tang2,6, Yi Chen2,6, Yan Fang2,6, Xiaoyun Lu3, Meiyu Geng2,5,6, Ke Ding3✉, Ker Yu1✉, Jian Ding1,2,5,6✉, Hua Xie2,4,5,6✉

1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
5. Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
6. University of Chinese Academy of Sciences, Beijing 100049, China.
*These authors contributed equally to this work.

Citation:
Lai M, Zhang T, Chen H, Song P, Tong L, Chen J, Liu Y, Ning Y, Feng F, Li Y, Tang H, Chen Y, Fang Y, Lu X, Geng M, Ding K, Yu K, Ding J, Xie H. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. J Cancer 2023; 14(1):152-162. doi:10.7150/jca.77788. https://www.jcancer.org/v14p0152.htm
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Abstract

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Osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), has significantly improved the survival of non-small cell lung cancer (NSCLC) patients with EGFRT790M mutation, the major mechanism of acquired resistance to first-generation EGFR TKI. However, resistance to AZD9291 arises eventually and EGFRC797S mutation was reported to be a major resistance mechanism. Thus, it is highly valuable to develop novel EGFR fourth-generation inhibitors targeting C797S mutation to override the acquired resistance. In this study, we identified HCD3514 as a novel EGFR fourth-generation inhibitors targeting C797S triple mutation. It strongly inhibited EGFRL858R/T790M/C797S and EGFR19del/T790M/C797S mutations with IC50 values of 1.0 and 2.0 nM, respectively. HCD3514 dose-dependently inhibited the activation of EGFR in both engineered BaF3 cells and tumor cells harboring EGFRC797S triple mutant and thus effectively suppressed the proliferation of the cells. Moreover, HCD3514 caused a dose-dependent increase of apoptosis in C797S triple mutant cells accompanied by increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, HCD3514 induced tumor growth inhibition in EGFR19del/T790M/C797S xenograft model as a single oral agent by decreasing the activation of EGFR. In addition to EGFRC797S triple mutations, HCD3514 also potently and selectively inhibited EGFRT790M double mutations (L858R/T790M and 19del/T790M). Collectively, HCD3514 is a highly selective and potent EGFR inhibitor against EGFRC797S triple mutations as well as EGFRT790M double mutations and is confirmed potently anti-tumor activity in preclinical models.

Keywords: fourth-generation EGFR inhibitor, EGFRC797S mutation, NSCLC, drug resistance, small molecular inhibitor


Citation styles

APA
Lai, M., Zhang, T., Chen, H., Song, P., Tong, L., Chen, J., Liu, Y., Ning, Y., Feng, F., Li, Y., Tang, H., Chen, Y., Fang, Y., Lu, X., Geng, M., Ding, K., Yu, K., Ding, J., Xie, H. (2023). Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. Journal of Cancer, 14(1), 152-162. https://doi.org/10.7150/jca.77788.

ACS
Lai, M.; Zhang, T.; Chen, H.; Song, P.; Tong, L.; Chen, J.; Liu, Y.; Ning, Y.; Feng, F.; Li, Y.; Tang, H.; Chen, Y.; Fang, Y.; Lu, X.; Geng, M.; Ding, K.; Yu, K.; Ding, J.; Xie, H. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. J. Cancer 2023, 14 (1), 152-162. DOI: 10.7150/jca.77788.

NLM
Lai M, Zhang T, Chen H, Song P, Tong L, Chen J, Liu Y, Ning Y, Feng F, Li Y, Tang H, Chen Y, Fang Y, Lu X, Geng M, Ding K, Yu K, Ding J, Xie H. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. J Cancer 2023; 14(1):152-162. doi:10.7150/jca.77788. https://www.jcancer.org/v14p0152.htm

CSE
Lai M, Zhang T, Chen H, Song P, Tong L, Chen J, Liu Y, Ning Y, Feng F, Li Y, Tang H, Chen Y, Fang Y, Lu X, Geng M, Ding K, Yu K, Ding J, Xie H. 2023. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. J Cancer. 14(1):152-162.

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