Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, United Kingdom.
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, United Kingdom.
Prog Med Chem. 2021;60:67-190. doi: 10.1016/bs.pmch.2021.01.002. Epub 2021 Mar 27.
The vast majority of currently marketed drugs rely on small molecules with an 'occupancy-driven' mechanism of action (MOA). Therefore, the efficacy of these therapeutics depends on a high degree of target engagement, which often requires high dosages and enhanced drug exposure at the target site, thus increasing the risk of off-target toxicities (Churcher, 2018 [1]). Although small molecule drugs have been successfully used as treatments for decades, tackling a variety of disease-relevant targets with a defined binding site, many relevant therapeutic targets remain challenging to drug due, for example, to lack of well-defined binding pockets or large protein-protein interaction (PPI) interfaces which resist interference (Dang et al., 2017 [2]). In the quest for alternative therapeutic approaches to address different pathologies and achieve enhanced efficacy with reduced side effects, ligand-induced targeted protein degradation (TPD) has gained the attention of many research groups both in academia and in industry in the last two decades. This therapeutic modality represents a novel paradigm compared to conventional small-molecule inhibitors. To pursue this strategy, heterobifunctional small molecule degraders, termed PROteolysis TArgeting Chimeras (PROTACs) have been devised to artificially redirect a protein of interest (POI) to the cellular protein homeostasis machinery for proteasomal degradation (Chamberlain et al., 2019 [3]). In this chapter, the development of PROTACs will first be discussed providing a historical perspective in parallel to the experimental progress made to understand this novel therapeutic modality. Furthermore, common strategies for PROTAC design, including assays and troubleshooting tips will be provided for the reader, before presenting a compendium of all PROTAC targets reported in the literature to date. Due to the recent advancement of these molecules into clinical trials, consideration of pharmacokinetics and pharmacodynamic properties will be introduced, together with the biotech landscape that has developed from the success of PROTACs. Finally, an overview of subsequent strategies for targeted protein degradation will be presented, concluding with further scientific quests triggered by the invention of PROTACs.
目前市场上绝大多数药物都依赖于具有“占据驱动”作用机制（MOA）的小分子。因此，这些疗法的疗效取决于靶标的高度结合，这通常需要高剂量和增强药物在靶部位的暴露，从而增加了脱靶毒性的风险（Churcher，2018 [1]）。尽管小分子药物已成功用于治疗数十年，可用于治疗多种与疾病相关的靶点，但由于缺乏明确的结合口袋或大的蛋白质-蛋白质相互作用（PPI）界面等原因，许多相关的治疗靶点仍然难以成为药物靶点，这些界面抵制干扰（Dang 等人，2017 [2]）。在寻求替代治疗方法来解决不同的病理问题并实现增强疗效和降低副作用的过程中，配体诱导的靶向蛋白降解（TPD）在过去二十年中引起了学术界和工业界许多研究小组的关注。与传统的小分子抑制剂相比，这种治疗模式代表了一种新的范例。为了追求这种策略，设计了杂双功能小分子降解剂，称为蛋白水解靶向嵌合体（PROTACs），以人为地将感兴趣的蛋白质（POI）重新定向到细胞蛋白质稳态机制，用于蛋白酶体降解（Chamberlain 等人，2019 [3]）。在本章中，将首先讨论 PROTACs 的发展，同时提供历史背景，以及为了理解这种新的治疗模式而取得的实验进展。此外，将为读者提供 PROTAC 设计的常见策略，包括测定法和故障排除技巧，然后介绍迄今为止文献中报道的所有 PROTAC 靶标摘要。由于这些分子最近已进入临床试验，因此将介绍药代动力学和药效学特性的考虑因素，以及 PROTAC 成功带来的生物技术发展。最后，将介绍靶向蛋白降解的后续策略概述，以 PROTACs 的发明为触发点，得出进一步的科学探索。
