The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, China.
The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1667-1693. doi: 10.1080/14756366.2022.2076675.
Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.
蛋白水解靶向嵌合体（PROTACs）作为一种新兴的靶向蛋白降解技术，引起了学术机构、大型制药企业和生物技术公司的关注。其作用机制是基于利用泛素 E3 连接酶劫持来抑制蛋白功能，从而实现蛋白降解。这种杂合双功能 PROTACs 包含一个募集 E3 连接酶的配体、一个连接子和另一个与目标降解蛋白结合的配体。迄今为止，已经成功开发了针对约 70 种蛋白的 PROTACs，其中许多是经过临床验证的药物靶点，并有几种正在临床试验中用于疾病治疗。在这篇综述中，总结了针对经过临床验证的药物靶点的 PROTACs 的最新进展，并强调了这些 PROTACs 的化学结构、细胞和活性、药代动力学和药效动力学。此外，还讨论了 PROTACs 技术在疾病治疗中的潜在优势、挑战和前景。
