Osman Jeyan, Thompson Philip E, Jörg Manuela, Scanlon Martin J
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
ARC Training Centre for Fragment Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Biochem J. 2025 Jun 25;482(13):BCJ20243018. doi: 10.1042/BCJ20243018.
Proteolysis-targeting chimeras (PROTACs) represent a novel and promising modality for probing biological systems, elucidating pharmacological mechanisms, and identifying potential therapeutic leads. The field has made significant strides, as demonstrated by the growing number of PROTACs advancing to clinical trials. Despite this progress, the development of PROTACs faces significant challenges, which is partially due to the heterobivalent nature of this class of molecules. PROTACs must simultaneously bind to a protein of interest and an E3 ubiquitin ligase. This means PROTACs are significantly larger and more complex than conventional small molecules. This complexity impacts their design and synthesis, requiring strategic approaches to create libraries of PROTACs with various combinations of target ligands, linkers, and E3 ligase-recruiting elements. To fully realise the potential of this innovative technology, there is a need for novel approaches to accelerate the development of PROTACs. This review focuses on three critical areas to accelerate PROTAC development: appropriate target selection, modular chemical synthesis, and high-throughput biological evaluation. By appropriate selection of target proteins for degradation, optimizing synthesis methods to handle the complexity of PROTAC molecules, and employing robust high-throughput biological assays to evaluate PROTAC activity, researchers in academia and industry have streamlined the development and increased the success rate of PROTAC-based discovery programmes.
靶向蛋白降解嵌合体（PROTACs）是一种用于探索生物系统、阐明药理机制和识别潜在治疗先导物的新颖且有前景的方法。该领域已取得重大进展，越来越多的PROTACs进入临床试验就证明了这一点。尽管取得了这一进展，但PROTACs的开发仍面临重大挑战，部分原因在于这类分子的异二价性质。PROTACs必须同时与目标蛋白和E3泛素连接酶结合。这意味着PROTACs比传统小分子要大得多且复杂得多。这种复杂性影响了它们的设计和合成，需要采用战略方法来创建具有各种目标配体、连接子和E3连接酶招募元件组合的PROTACs文库。为了充分实现这项创新技术的潜力，需要有新颖的方法来加速PROTACs的开发。本综述重点关注加速PROTAC开发的三个关键领域：合适的靶点选择、模块化化学合成和高通量生物学评估。通过适当选择用于降解的目标蛋白、优化合成方法以应对PROTAC分子的复杂性，并采用强大的高通量生物学检测来评估PROTAC活性，学术界和工业界的研究人员简化了开发过程，提高了基于PROTAC的发现计划的成功率。
