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

文献类型：期刊论文

作者Lai, Mengzhen3,4; Zhang, Tao4; Chen, Hao5; Song, Peiran4,6; Tong, Linjiang4; Chen, Jiaying1,4; Liu, Yingqiang4; Ning, Yi1,4; Feng, Fang4; Li, Yan4
刊名JOURNAL OF CANCER
出版日期2023
卷号14期号:1页码:152-162
关键词fourth-generation EGFR inhibitor EGFRC797S mutation NSCLC drug resistance small molecular inhibitor
ISSN号1837-9664
DOI10.7150/jca.77788
通讯作者Ding, Ke(dingke@jnu.edu.cn) ; Yu, Ker(keryu@fudan.edu.cn) ; Ding, Jian(jding@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn)
英文摘要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.
WOS关键词CELL LUNG-CANCER ; FACTOR RECEPTOR INHIBITORS ; ACQUIRED-RESISTANCE ; ACTIVATING MUTATIONS ; OPEN-LABEL ; MECHANISMS ; EFFICACY ; MULTICENTER ; AZD9291 ; SAFETY
资助项目Lingang Laboratory[LG202103-02-02] ; National Natural Science Foundation of China[82273948] ; National Natural Science Foundation of China[81903638] ; National Natural Science Foundation of China[81922062] ; Opening Foundation from State Key Laboratory of Drug Research[SIMM2205KF-09] ; High-level new R&D Institute, Department of Science and Technology of Guangdong Province[2019B090904008] ; High-level Innovative Research Institute, Department of Science and Technology of Guangdong Province[2021B0909050003]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000908928500003
出版者IVYSPRING INT PUBL
源URL[http://119.78.100.183/handle/2S10ELR8/303790]  
专题新药研究国家重点实验室
通讯作者Ding, Ke; Yu, Ker; Ding, Jian; Xie, Hua
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Chinese Minist Educ MOE,Guangzhou City Key Lab Pre, Guangzhou 510632, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Lai, Mengzhen,Zhang, Tao,Chen, Hao,et al. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo[J]. JOURNAL OF CANCER,2023,14(1):152-162.
APA Lai, Mengzhen.,Zhang, Tao.,Chen, Hao.,Song, Peiran.,Tong, Linjiang.,...&Xie, Hua.(2023).Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo.JOURNAL OF CANCER,14(1),152-162.
MLA Lai, Mengzhen,et al."Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo".JOURNAL OF CANCER 14.1(2023):152-162.

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来源：上海药物研究所

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