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

被引：60

作者：

Zhou, Chuan ^{[1
]}

Fan, Zisheng ^{[2
,3
]}

Zhou, Zehui ^{[1
,4
]}

Li, Yupeng ^{[5
,6
]}

Cui, Rongrong ^{[2
,3
]}

Liu, Chaoyi ^{[1
]}

Zhou, Guizhen ^{[2
,3
]}

Diao, Xingxing ^{[7
]}

Jiang, Hualiang ^{[2
,3
,4
,8
]}

Zheng, Mingyue ^{[2
,3
,4
,8
]}

Zhang, Sulin ^{[3
,4
]}

Xu, Tianfeng ^{[1
,4
,8
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China

[2] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China

[3] Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[5] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA

[6] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA

[7] Chinese Acad Sci, Shanghai Ctr Drug Metab & Pharmacokinet, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[8] Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 05期

基金：

中国国家自然科学基金; 上海市自然科学基金; 中国博士后科学基金;

关键词：

PROTEIN-DEGRADATION; RAS;

D O I：

10.1021/acs.jmedchem.1c01774

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：3923 / 3942

页数：20

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