Degradation of Rat Sarcoma Proteins Targeting the Post-Translational Prenyl Modifications via Cascade Azidation/Fluorination and Click Reaction,Journal of Medicinal Chemistry

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Degradation of Rat Sarcoma Proteins Targeting the Post-Translational Prenyl Modifications via Cascade Azidation/Fluorination and Click Reaction
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-19 , DOI: 10.1021/acs.jmedchem.2c01721
Hongling Zhou _{1,

2} , Youfang Gan ₁ , Yuanyuan Li ₁ , Xiaoqian Chen ₁ , Yuyang Guo ₁ , Rui Wang _{1,

2}

Affiliation

Protein degradation is emerging as a powerful strategy to modulate protein functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used to degrade a range of “undruggable” proteins in cells. Here, we present a type of chemically catalyzed PROTAC to induce rat sarcoma (RAS) degradation based on the chemistry of post-translational prenyl modification. Trimethylsilyl azide and Selectfluor were used to chemically tag the prenyl modification on Caax motif of RAS protein, and a sequential click reaction was applied using the propargyl pomalidomide probe to degrade the prenylated RAS in several cells. Thus, this approach was successfully applied to degrade RAS in multiple cancer cell lines including HeLa, HEK 293T, A549, MCF-7, and HT-29. This novel approach targeting RAS’s post-translational prenyl modification to induce RAS degradation by employing the sequential azidation/fluorination and click reaction has been demonstrated efficiently and highly selectively, expanding PROTAC toolsets in the study of disease-relevant protein targets.

中文翻译：

通过级联叠氮/氟化和点击反应降解针对翻译后异戊烯基修饰的大鼠肉瘤蛋白

蛋白质降解正在成为调节蛋白质功能和改变细胞信号传导途径的强大策略。蛋白水解靶向嵌合体（PROTAC）已被用来降解细胞中一系列“不可成药”的蛋白质。在这里，我们提出了一种基于翻译后异戊二烯基修饰的化学催化 PROTAC 来诱导大鼠肉瘤 (RAS) 降解。使用三甲基硅基叠氮化物和 Selectflor 对 RAS 蛋白 Caax 基序上的异戊二烯基修饰进行化学标记，并使用炔丙基泊马度胺探针进行连续点击反应，以降解多个细胞中异戊二烯化的 RAS。因此，该方法成功应用于降解多种癌细胞系中的 RAS，包括 HeLa、HEK 293T、A549、MCF-7 和 HT-29。

更新日期：2023-05-19

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