Troup Robert I, Fallan Charlene, Baud Matthias G J
School of Chemistry, University of Southampton, Highfield, SO17 1BJ Southampton, UK.
Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge Science Park, Milton Road, CB4 0WG Cambridge, UK.
Explor Target Antitumor Ther. 2020;1(5):273-312. doi: 10.37349/etat.2020.00018. Epub 2020 Oct 30.
PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an "anchor" to bind to an E3 ubiquitin ligase and a "warhead" to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional "trial and error" approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.
蛋白酶靶向嵌合体（PROTACs）是由两个配体组成的异双功能分子；一个与E3泛素连接酶结合的“锚定基团”和一个与目标蛋白结合的“弹头”，通过化学连接子相连。PROTACs介导的靶向蛋白降解已成为一种敲低一系列蛋白质的新方式，首批药物现已进入临床评估阶段。越来越清楚的是，连接子的长度和组成对PROTACs的物理化学性质和生物活性起着关键作用。虽然连接子设计在历史上受到的关注有限，但PROTAC领域正在迅速发展，目前正经历从易于合成的烷基和聚乙二醇向更复杂的功能性连接子的重要转变。这有望解锁大量具有增强生物活性的新型PROTAC药物用于治疗干预。在此，作者及时概述了已发表文献中不同类型的连接子，以及它们的基本设计原则和对相关PROTACs性质和生物活性的总体影响。最后，作者对PROTAC组装的当前策略进行了批判性分析。作者强调了围绕连接子设计和选择的传统“试错”方法存在的重要局限性，并提出了潜在的未来途径，以进一步指导合理的连接子设计并加速优化PROTACs的鉴定。特别是，作者认为计算和结构方法的进步将在更好地理解PROTAC三元复合物的结构和动力学方面发挥重要作用，并且对于解决当前与PROTAC设计相关的知识空白至关重要。
