Luo Hang, Wu Li, He Yujian, Qin Chong, Tang Xinjing
School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Front Cell Dev Biol. 2022 Jun 22;10:921958. doi: 10.3389/fcell.2022.921958. eCollection 2022.
Recently, degrader technologies have attracted increasing interest in the academic field and the pharmaceuticals industry. As one of the degrader technologies, proteolysis-targeting chimeras (PROTACs) have emerged as an attractive pharmaceutical development approach due to their catalytic ability to degrade numerous undruggable disease-causing proteins. Despite the remarkable progress, many aspects of traditional PROTACs still remain elusive. Its expansion could lead to PROTACs with new paradigm. Currently, many reviews focused on the design and optimization strategies through summarizing classical PROTACs, application in diseases and prospect of PROTACs. In this review, we categorize various emerging PROTACs ranging from simply modified classical PROTACs to atypical PROTACs such as nucleic acid-based PROTACs, and we put more emphasis on molecular design of PROTACs with different strategies. Furthermore, we summarize alternatives of PROTACs as lysosome-targeting chimeras (LYTACs) and macroautophagy degradation targeting chimeras (MADTACs) based on different degradation mechanism despite of lysosomal pathway. Beyond these protein degraders, targeting RNA degradation with the potential for cancer and virus therapeutics has been discussed. In doing so, we provide our perspective on the potential development or concerns of each degrader technology. Overall, we hope this review will offer a better mechanistic understanding of emerging degraders and prove as useful guide for the development of the coming degrader technologies.
近年来，降解技术在学术领域和制药行业引起了越来越多的关注。作为降解技术之一，蛋白酶靶向嵌合体（PROTACs）因其能够催化降解众多难以成药的致病蛋白，已成为一种颇具吸引力的药物开发方法。尽管取得了显著进展，但传统PROTACs的许多方面仍不明确。其扩展可能会带来具有新范式的PROTACs。目前，许多综述通过总结经典PROTACs、在疾病中的应用以及PROTACs的前景，聚焦于设计和优化策略。在本综述中，我们将各种新兴的PROTACs进行分类，从简单修饰的经典PROTACs到非典型PROTACs，如基于核酸的PROTACs，并更强调采用不同策略的PROTACs的分子设计。此外，我们总结了PROTACs的替代物，即基于不同降解机制的溶酶体靶向嵌合体（LYTACs）和巨自噬降解靶向嵌合体（MADTACs），尽管是通过溶酶体途径。除了这些蛋白质降解剂，还讨论了具有癌症和病毒治疗潜力的靶向RNA降解。通过这样做，我们对每种降解技术的潜在发展或关注点提出了自己的看法。总体而言，我们希望本综述能提供对新兴降解剂更好的机制理解，并为未来降解技术的发展提供有用的指导。
