清华大学李景虹团队报道了用于肿瘤选择性蛋白降解和靶向癌症治疗的ClickRNA-PROTAC。相关研究成果发表在2024年9月25日出版的《美国化学会杂志》。

蛋白水解靶向嵌合体（PROTACs）在肿瘤治疗中具有前景。然而，PROTAC中常用的E3连接酶VHL和CRBN仅在少数肿瘤中高度表达，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可能会导致毒副作用。因此，迫切需要开发不依赖内源性E3连接酶的肿瘤选择性PROTAC药物。

该文中，研究人员介绍了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，并使用生物正交点击化学招募感兴趣的蛋白质（POI）。

ClickRNA-PROTAC可以通过替换弹头分子来有效降解各种蛋白质，如BRD4、KRAS和NFκB。通过采用肿瘤特异性mRNA反应翻译策略，ClickRNA-PROTAC可以选择性降解肿瘤细胞中的POI。此外，在肾上腺皮质癌异种移植小鼠模型中，ClickRNA-PROTAC在靶向癌症治疗中表现出强大的疗效。

总之，这种方法具有几个优点，包括独立于内源性E3泛素连接酶、肿瘤特异性和可编程性，从而为PROTAC药物的开发铺平了道路。

附：英文原文

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

Author: Xucong Teng, Xuan Zhao, Yicong Dai, Xiangdong Zhang, Qiushuang Zhang, Yuncong Wu, Difei Hu, Jinghong Li

Issue&Volume: September 25, 2024

Abstract: 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.

DOI: 10.1021/jacs.4c06402

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c06402