Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers
文献类型：期刊论文
| 作者 | Zhou, Zehui3,6; Zhou, Guizhen5,7; Zhou, Chuan3; Fan, Zisheng7; Cui, Rongrong7 ; Li, Yupeng1,2; Li, Rui7; Gu, Yuejiao3,6; Li, Huajie4; Ge, Zhiming4
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-03-23 |
| 卷号 | 66期号:6页码:4197-4214 |
| DOI | 10.1021/acs.jmedchem.3c00075 |
| 文献子类 | Article |
| 英文摘要 | The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants. |
| WOS关键词 | PROTEOLYSIS-TARGETING CHIMERAS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000950124400001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309674]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zheng, Mingyue; Xu, Tianfeng; Zhang, Sulin |
| 作者单位 | 1.Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA 2.Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China; 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhou, Zehui,Zhou, Guizhen,Zhou, Chuan,et al. Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(6):4197-4214. |
| APA | Zhou, Zehui.,Zhou, Guizhen.,Zhou, Chuan.,Fan, Zisheng.,Cui, Rongrong.,...&Zhang, Sulin.(2023).Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.JOURNAL OF MEDICINAL CHEMISTRY,66(6),4197-4214. |
| MLA | Zhou, Zehui,et al."Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers".JOURNAL OF MEDICINAL CHEMISTRY 66.6(2023):4197-4214. |
入库方式： OAI收割
来源：上海药物研究所
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