The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao, 266071, Shandong, China; School of Pharmacy, Qingdao University, Qingdao, 266021, Shandong, China.
Eur J Med Chem. 2022 Jan 5;227:113906. doi: 10.1016/j.ejmech.2021.113906. Epub 2021 Oct 9.
Proteolysis targeting chimeras (PROTACs), which hijack proteins of interest (POIs) and recruit E3 ligases for target degradation via the ubiquitin-proteasome pathway, are a novel drug discovery paradigm that has been widely used as biological tools and medicinal molecules with the potential of clinical application value. To date, a wide variety of small molecule PROTACs have been developed. Importantly, VHL-based PROTACs have emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. VHL-based PRTOACs have been developed for the treatment of diseases that are difficult to be dealt with by conventional methods, such as radiotherapy, chemotherapy, and small molecule inhibitors. In this review, the recent advances of VHL-based PRTOACs were summarized, and the chances and challenges associated with this area were also highlighted.
蛋白水解靶向嵌合体（PROTACs）通过泛素-蛋白酶体途径劫持靶蛋白（POIs）并招募 E3 连接酶进行目标降解，是一种新的药物发现范式，已被广泛用作生物工具和具有临床应用价值的药物分子。迄今为止，已经开发了多种小分子 PROTACs。重要的是，基于 VHL 的 PROTACs 已成为一种有前途的方法，可用于治疗包括转录因子和支架蛋白等难以成药的蛋白质。已经开发了基于 VHL 的 PROTACs 来治疗传统方法难以处理的疾病，如放疗、化疗和小分子抑制剂。在这篇综述中，总结了基于 VHL 的 PROTACs 的最新进展，并强调了该领域的机遇和挑战。
