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Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

文献类型：期刊论文

作者Zhou, Chuan2; Fan, Zisheng3,4; Zhou, Zehui2,5; Li, Yupeng6,7; Cui, Rongrong3,4; Liu, Chaoyi2; Zhou, Guizhen3,4; Diao, Xingxing1; Jiang, Hualiang3,4,5,8; Zheng, Mingyue3,4,5,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-03-10
卷号65期号:5页码:3923-3942
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01774
通讯作者Zheng, Mingyue(myzheng@simm.ac.cn) ; Zhang, Sulin(slzhang@simm.ac.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.
WOS关键词PROTEIN-DEGRADATION ; RAS
资助项目Natural Science Foundation of Shanghai[20ZR1468500] ; Shanghai Pujiang Program[19PJ1411400] ; National Natural Science Foundation of China[81903639] ; Lingang Laboratory[LG202102-01-02] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Sailing Program[19YF1457800] ; China Postdoctoral Science Foundation[2021M693270]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000772205900015
源URL[http://119.78.100.183/handle/2S10ELR8/299906]  
专题新药研究国家重点实验室
通讯作者Zheng, Mingyue; Zhang, Sulin; Xu, Tianfeng
作者单位1.Chinese Acad Sci, Shanghai Ctr Drug Metab & Pharmacokinet, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA
7.Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
8.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Chuan,Fan, Zisheng,Zhou, Zehui,et al. Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(5):3923-3942.
APA Zhou, Chuan.,Fan, Zisheng.,Zhou, Zehui.,Li, Yupeng.,Cui, Rongrong.,...&Xu, Tianfeng.(2022).Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations.JOURNAL OF MEDICINAL CHEMISTRY,65(5),3923-3942.
MLA Zhou, Chuan,et al."Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations".JOURNAL OF MEDICINAL CHEMISTRY 65.5(2022):3923-3942.

入库方式： OAI收割

来源：上海药物研究所

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