Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers,Journal of Medicinal Chemistry

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Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-03-10 , DOI: 10.1021/acs.jmedchem.3c00075
Zehui Zhou _{1,

2} , Guizhen Zhou _{3,

4} , Chuan Zhou ₁ , Zisheng Fan ₃ , Rongrong Cui ₃ , Yupeng Li ₅ , Rui Li ₃ , Yuejiao Gu _{1,

2} , Huajie Li ₆ , Zhiming Ge ₆ , Xiaojia Cai _{1,

2} , Bing Jiang _{3,

4} , Dan Wang _{3,

4} , Mingyue Zheng _{2,

3,

4,

6} , Tianfeng Xu _{1,

2,

6} , Sulin Zhang _{2,

3}

Affiliation

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 KRAS^G12D- and ^G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

中文翻译：

发现在 KRAS 突变癌症中具有体内抗肿瘤功效的强效、协同和选择性 SOS1 PROTAC ZZ151

蛋白水解靶向嵌合体 (PROTAC) 分子的接头部分在调节降解活性、目标选择性和物理化学性质方面起着关键作用。然而，导致 PROTAC 降解活性发生显着变化的接头结构化学修饰的基础知识和潜在机制值得进一步研究。在此，我们报告了一种高效且具有选择性的 SOS1 PROTAC ZZ151 的设计和表征。在系统地修改接头长度和组成后，我们观察到仅对 ZZ151 接头部分的一个原子进行细微修改就会导致三元复合物的形成发生显着变化，从而显着影响降解活性。ZZ151快速、特异、有效地诱导SOS1降解；对广泛的 KRAS 突变驱动的癌细胞表现出有效的抗增殖活性；并在 KRAS 中表现出优异的抗癌活性^{小鼠中的G12D} - 和^{G12V -}突变异种移植物。ZZ151 是开发针对 KRAS 突变体的新化学疗法的有前途的先导。

更新日期：2023-03-10

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