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Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

文献类型：期刊论文

作者Zhang, Hualin3,4; Xie, Ruliang4; AI-furas, Hawaa5; Li, Yupeng6,7; Wu, Qingxia4; Li, Jian3; Xu, Fang5; Xu, Tianfeng1,2,4
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2022-02-10
卷号13期号:2页码:278-283
关键词NSCLC acquired resistance EGFR C797S PROTACs selectivity
ISSN号1948-5875
DOI10.1021/acsmedchemlett.1c00645
通讯作者Li, Jian(lijian@shu.edu.cn) ; Xu, Fang(xufang@jnu.edu.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR(Del19/T79M/C797S )mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC50 of 8 nM. It also showed good antiproliferation activity (IC50 = 0.02 mu M) against Ba/F3-EGFR(Del19/T790M/C797S) cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.
WOS关键词CELL LUNG-CANCER ; ACQUIRED-RESISTANCE ; DEGRADATION ; INHIBITORS
资助项目Shanghai Pujiang Program[19PJ1411400] ; National Natural Science Foundation of China[21807044]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000755513000023
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/300342]  
专题中国科学院上海药物研究所
通讯作者Li, Jian; Xu, Fang; Xu, Tianfeng
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
5.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat &, Guangzhou City Key Lab Precis Chem Drug Dev,Minis, Guangzhou 510632, Peoples R China
6.Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA
7.Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
推荐引用方式
GB/T 7714		 Zhang, Hualin,Xie, Ruliang,AI-furas, Hawaa,et al. Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation[J]. ACS MEDICINAL CHEMISTRY LETTERS,2022,13(2):278-283.
APA Zhang, Hualin.,Xie, Ruliang.,AI-furas, Hawaa.,Li, Yupeng.,Wu, Qingxia.,...&Xu, Tianfeng.(2022).Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation.ACS MEDICINAL CHEMISTRY LETTERS,13(2),278-283.
MLA Zhang, Hualin,et al."Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation".ACS MEDICINAL CHEMISTRY LETTERS 13.2(2022):278-283.

入库方式： OAI收割

来源：上海药物研究所

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