Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation <i>in vitro</i> and <i>in vivo</i>

Lai, Mengzhen; Zhang, Tao; Chen, Hao; Song, Peiran; Tong, Linjiang; Chen, Jiaying; Liu, Yingqiang; Ning, Yi; Feng, Fang; Li, Yan; Tang, Haotian; Chen, Yi; Fang, Yan; Lu, Xiaoyun; Geng, Meiyu; Ding, Ke; Yu, Ker; Ding, Jian; Xie, Hua

doi:10.7150/jca.77788

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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 Lai^1,2*, Tao Zhang^2*, Hao Chen^3*, Peiran Song^2,4*, Linjiang Tong², Jiaying Chen^2,6, Yingqiang Liu², Yi Ning^2,6, Fang Feng², Yan Li², Haotian Tang^2,6, Yi Chen^2,6, Yan Fang^2,6, Xiaoyun Lu³, Meiyu Geng^2,5,6, Ke Ding^3✉, Ker Yu^1✉, Jian Ding^1,2,5,6✉, Hua Xie^2,4,5,6✉

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

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 EGFR^T790M mutation, the major mechanism of acquired resistance to first-generation EGFR TKI. However, resistance to AZD9291 arises eventually and EGFR^C797S 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 EGFR^{L858R/T790M/C797S} and EGFR^{19del/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 EGFR^C797S 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 EGFR^{19del/T790M/C797S} xenograft model as a single oral agent by decreasing the activation of EGFR. In addition to EGFR^C797S triple mutations, HCD3514 also potently and selectively inhibited EGFR^T790M double mutations (L858R/T790M and 19del/T790M). Collectively, HCD3514 is a highly selective and potent EGFR inhibitor against EGFR^C797S triple mutations as well as EGFR^T790M double mutations and is confirmed potently anti-tumor activity in preclinical models.

Keywords: fourth-generation EGFR inhibitor, EGFR^C797S mutation, NSCLC, drug resistance, small molecular inhibitor

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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

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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