用于肿瘤选择性蛋白降解和癌症靶向治疗的 ClickRNA-PROTAC

IF 15.6 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Xucong Teng, Xuan Zhao, Yicong Dai, Xiangdong Zhang, Qiushuang Zhang, Yuncong Wu, Difei Hu and Jinghong Li*, 
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引用次数: 0

摘要

蛋白水解靶向嵌合体(PROTACs)在肿瘤治疗中大有可为。然而,PROTAC常用的E3连接酶VHL和CRBN仅在少数肿瘤中高表达,从而限制了PROTAC药物的应用范围和疗效。此外,PROTAC 药物缺乏肿瘤特异性会导致毒副作用。因此,开发不依赖内源性 E3 连接酶的肿瘤选择性 PROTAC 药物迫在眉睫。在这项研究中,我们引入了 ClickRNA-PROTAC 系统,该系统通过 mRNA 转染表达 E3 泛素连接酶 SIAH1 和 SNAPTag 的融合蛋白,并利用生物正交点击化学方法诱导感兴趣的蛋白(POI)。只需更换弹头分子,ClickRNA-PROTAC 就能有效降解 BRD4、KRAS 和 NFκB 等多种蛋白质。通过采用肿瘤特异性 mRNA 响应翻译策略,ClickRNA-PROTAC 可以选择性地降解肿瘤细胞中的 POIs。此外,在肾上腺皮质癌异种移植小鼠模型中,ClickRNA-PROTAC 在癌症靶向治疗中显示出强大的疗效。总之,这种方法具有独立于内源性E3泛素连接酶、肿瘤特异性和可编程性等优点,从而为开发PROTAC药物铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy

ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) show promise in tumor treatment. However, the E3 ligases VHL and CRBN, commonly used in PROTAC, are highly expressed in only a few tumors, thus limiting the application scope and efficacy of PROTAC drugs. Furthermore, the lack of tumor specificity in PROTAC drugs can result in toxic side effects. Therefore, there is an urgent need to develop tumor-selective PROTAC drugs that do not rely on endogenous E3 ligases. In this study, we introduce the ClickRNA-PROTAC system, which involves the expression of a fusion protein of the E3 ubiquitin ligase SIAH1 and SNAPTag through mRNA transfection and recruits the protein of interest (POI) using bio-orthogonal click chemistry. ClickRNA-PROTAC can effectively degrade various proteins such as BRD4, KRAS, and NFκB simply by replacing the warhead molecules. By employing a tumor-specific mRNA-responsive translation strategy, ClickRNA-PROTAC can selectively degrade POIs in tumor cells. Furthermore, ClickRNA-PROTAC demonstrated strong efficacy in targeted cancer therapy in a xenograft mouse model of adrenocortical carcinoma. In conclusion, this approach offers several advantages, including independence from endogenous E3 ubiquitin ligases, tumor specificity, and programmability, thereby paving the way for the development of PROTAC drugs.

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来源期刊
CiteScore
24.40
自引率
6.00%
发文量
2398
审稿时长
1.6 months
期刊介绍: The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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