Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, China.
Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, China.
Eur J Med Chem. 2023 Dec 5;261:115793. doi: 10.1016/j.ejmech.2023.115793. Epub 2023 Sep 7.
Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.
蛋白水解靶向嵌合体（PROTACs）是一个研究热点，具有拓展药物空间的潜力，而不局限于传统分子。在过去的五年中，我们已经见证了多个 PROTACs 进入 I/II/III 期临床试验，这给了我们很大的启发。然而，PROTACs 的结构超出了“五规则”，导致开发具有可接受口服药代动力学（PK）性质的 PROTACs 仍然是最大的瓶颈任务之一。许多报告表明，通过合理的配体和连接子修饰，有可能获得口服生物利用的 PROTACs。在这篇综述中，我们系统地回顾和强调了口服生物利用的 PROTACs 开发的最新进展，特别是集中在发现过程中的药物化学研究和体内口服 PK 性质上。此外，还全面提出了开发口服 PROTACs 的建设性策略。总的来说，我们相信这里总结的策略可以为口服 PROTACs 的进一步发展提供参考。
