Cornu Marie, Lemaitre Thomas, Kieffer Charline, Voisin-Chiret Anne Sophie
Université de Caen Normandie, CERMN UR4258, Normandie Université, F-14000 Caen, France.
Université de Caen Normandie, CERMN UR4258, Normandie Université, F-14000 Caen, France.
Drug Discov Today. 2025 Jun;30(6):104376. doi: 10.1016/j.drudis.2025.104376. Epub 2025 May 8.
Proteolysis targeting chimera (PROTAC) technology has revolutionized targeted protein degradation via the ubiquitin-proteasome system. Despite their efficacy in degrading previously undruggable proteins, classical PROTACs face challenges such as poor permeability, dose-dependent effects, and off-target toxicity, prompting the rise of next-generation PROTACs (PROTAC 2.0). This review explores emerging PROTAC-based strategies aimed at enhancing selectivity, bioavailability, and pharmacokinetics. We discuss innovative approaches such as photoactivable PROTACs, hypoxia-responsive degraders, dual and trivalent PROTACs, and antibody-conjugated degraders. Additionally, nanotechnology-based delivery systems are highlighted as promising tools to overcome membrane permeability issues. By analyzing these novel strategies, we highlight the evolution of PROTACs and their growing therapeutic potential. Advances in PROTAC 2.0 technologies are expected to expand their clinical applications, offering more selective and efficient degradation mechanisms.
蛋白酶靶向嵌合体（PROTAC）技术通过泛素-蛋白酶体系统彻底改变了靶向蛋白质降解。尽管经典PROTAC在降解以前难以成药的蛋白质方面具有功效，但它们面临着诸如通透性差、剂量依赖性效应和脱靶毒性等挑战，这促使了下一代PROTAC（PROTAC 2.0）的兴起。本综述探讨了旨在提高选择性、生物利用度和药代动力学的基于PROTAC的新兴策略。我们讨论了光活化PROTAC、缺氧响应性降解剂、双价和三价PROTAC以及抗体偶联降解剂等创新方法。此外，基于纳米技术的递送系统被视为克服膜通透性问题的有前景的工具。通过分析这些新策略，我们突出了PROTAC的发展及其不断增长的治疗潜力。预计PROTAC 2.0技术的进步将扩大其临床应用，提供更具选择性和高效的降解机制。
