He Yiting, Liao Tianzuo, Wang Xuan'er, Xiao Qian, Wang Hongmei, He Rui, Zhao Chenyu, Tian Xinmiao, Gao Qinghua, Hao Liying
China Medical University-Queen's University of Belfast Joint College, China Medical University, Shenyang 110122, China; School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China; The Second Clinical College of China Medical University, 110801, China.
Bioorg Chem. 2025 Aug 6;164:108846. doi: 10.1016/j.bioorg.2025.108846.
The Proteolysis Targeting Chimera (PROTAC) is one of the targeted protein degradation technologies, leveraging the ubiquitin-proteasome system to selectively degrade target proteins within cells. Unlike conventional therapies that rely on continuous occupancy of the target protein, PROTACs operate through an event-driven mechanism that enables catalytic protein degradation, achieving effects at sub-stoichiometric concentrations. This review compares PROTACs with small-molecule inhibitors and monoclonal antibodies (mAbs), highlighting their ability to degrade "undruggable" intracellular proteins, and potential to eliminate targets with high efficiency at low doses. We provide a detailed analysis of PROTAC-based drugs, covering development progress up to 2024 in six major disease areas, including oncology, autoimmune, cardiovascular, neurodegenerative, viral infections, and rare genetic diseases. However, PROTACs face challenges including E3 ligase limitation, systemic toxicity, and delivery inefficiencies. By exploring the stimulus-responsive PROTACs and Nano-PROTACs, we highlight their potential to improve delivery precision, enhance tissue specificity, reduce systemic toxicity, and overcome membrane permeability issues. Advances in PROTACs are expected to improve target specificity, expand the spectrum of druggable targets, and optimize pharmacokinetics, enabling safer and more efficient clinical therapies.
蛋白酶靶向嵌合体（PROTAC）是一种靶向蛋白质降解技术，它利用泛素-蛋白酶体系统在细胞内选择性降解靶蛋白。与依赖于持续占据靶蛋白的传统疗法不同，PROTAC通过一种事件驱动机制发挥作用，这种机制能够催化蛋白质降解，在亚化学计量浓度下实现效果。本综述将PROTAC与小分子抑制剂和单克隆抗体（mAb）进行了比较，强调了它们降解“不可成药”细胞内蛋白质的能力，以及在低剂量下高效消除靶点的潜力。我们对基于PROTAC的药物进行了详细分析，涵盖了截至2024年在六个主要疾病领域的开发进展，包括肿瘤学、自身免疫性疾病、心血管疾病、神经退行性疾病、病毒感染和罕见遗传病。然而，PROTAC面临着包括E3连接酶限制、全身毒性和递送效率低下等挑战。通过探索刺激响应性PROTAC和纳米PROTAC，我们强调了它们在提高递送精度、增强组织特异性、降低全身毒性和克服膜通透性问题方面的潜力。预计PROTAC的进展将提高靶点特异性，扩大可成药靶点范围，并优化药代动力学，从而实现更安全、更有效的临床治疗。
