Identification of Boc2Lys-Linked Ethacrynic Acid and Its Analogues As Efficient Glutathione S-Transferase Degraders

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-14 DOI:10.1021/acsmedchemlett.4c0027410.1021/acsmedchemlett.4c00274

Hui Sun, Cong Wang, Xiaona Li, Zirui Lü, Kebin Li, Hengjie Hu, Ping Xu, Yu Xiao* and Yan Niu*,

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Abstract

Targeted protein degradation has been emerging as a promising strategy for drug design and a useful tool for the research of intracellular protein function by specifically downregulating the protein level via promoted degradation. Aside from proteolysis targeting chimeras (PROTAC) that utilize a specific E3 ligase ligand as a tag to recruit polyubiquitin onto the targeted protein and subsequently induce degradation, Boc₃Arg was also reported an efficient tag to induce degradation through directly localizing the protein to the 20S proteasome. Based on the similarity of Boc₂Lys and Boc₃Arg, we identified that Boc₂Lys also efficiently induced targeted protein degradation, taking glutathione S-transferase as an example. We found that Boc₂Lys-linked ethacrynic acid was able to dose-dependently downregulate the target protein in a mechanism distinct to Boc₃Arg.

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鉴定 Boc2Lys 链接的乙酰丙酸及其类似物是否为高效的谷胱甘肽 S-转移酶降解剂

靶向蛋白质降解是一种很有前途的药物设计策略，也是通过促进降解特异性地降低蛋白质水平来研究细胞内蛋白质功能的有用工具。除了蛋白水解靶向嵌合体（PROTAC）利用特定的 E3 配体作为标签将多泛素募集到靶向蛋白上并随后诱导降解外，Boc3Arg 也被报道为一种有效的标签，通过直接将蛋白定位到 20S 蛋白酶体来诱导降解。基于 Boc2Lys 和 Boc3Arg 的相似性，我们以谷胱甘肽 S 转移酶为例，发现 Boc2Lys 也能有效诱导靶蛋白降解。我们发现，与 Boc2Lys 链接的乙基丙烯酸能够以一种不同于 Boc3Arg 的机制剂量依赖性地下调靶蛋白。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.