Wang Chao, Zhang Yujing, Wu Yudong, Xing Dongming
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.
Eur J Med Chem. 2021 Dec 5;225:113749. doi: 10.1016/j.ejmech.2021.113749. Epub 2021 Aug 10.
Protease-targeted chimeras (PROTACs) are a new technology that is receiving much attention in the treatment of diseases. The mechanism is to inhibit protein function by hijacking the ubiquitin E3 ligase for protein degradation. Heterogeneous bifunctional PROTACs contain a ligand for recruiting E3 ligase, a linker, and another ligand to bind to the target protein for degradation. A variety of small-molecule PROTACs (CRBN, VHL, IAPs, MDM2, DCAF15, DCAF16, and RNF114-based PROTACs) have been identified so far. In particular, CRBN-based PROTACs (e.g., ARV-110 and ARV-471) have received more attention for their promising therapeutic intervention. To date, CRBN-based PRTOACs have been extensively explored worldwide and have excelled not only in cancer diseases but also in cardiovascular diseases, immune diseases, neurodegenerative diseases, and viral infections. In this review, we will provide a comprehensive update on the latest research progress in CRBN-based PRTOACs area. Following the criteria, such as disease area and drug target class, we will present the degradants in alphabetical order by target. We also provide our own perspective on the future prospects and potential challenges facing PROTACs.
蛋白酶靶向嵌合体（PROTACs）是一种在疾病治疗中备受关注的新技术。其作用机制是通过劫持泛素E3连接酶来促进蛋白质降解，从而抑制蛋白质功能。异源双功能PROTACs包含一个用于招募E3连接酶的配体、一个连接子以及另一个与靶蛋白结合以进行降解的配体。到目前为止，已经鉴定出多种小分子PROTACs（基于CRBN、VHL、IAPs、MDM2、DCAF15、DCAF16和RNF114的PROTACs）。特别是，基于CRBN的PROTACs（如ARV - 110和ARV - 471）因其有前景的治疗干预效果而受到更多关注。迄今为止，基于CRBN的PROTACs在全球范围内得到了广泛研究，不仅在癌症疾病方面表现出色，在心血管疾病、免疫疾病、神经退行性疾病和病毒感染等方面也有良好效果。在这篇综述中，我们将全面更新基于CRBN的PROTACs领域的最新研究进展。按照疾病领域和药物靶点类别等标准，我们将按靶点字母顺序列出降解剂。我们还对PROTACs的未来前景和潜在挑战提出了自己的看法。
