Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
Signal Transduct Target Ther. 2024 Nov 6;9(1):308. doi: 10.1038/s41392-024-02004-x.
Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.
靶向蛋白降解（TPD）代表了疾病管理领域的一项革命性治疗策略，与传统的治疗方法（如主要专注于抑制蛋白质功能的小分子抑制剂）形成鲜明对比。这项先进技术利用了细胞内在的蛋白水解系统，包括蛋白酶体和溶酶体途径，以选择性地消除致病蛋白。TPD 不仅提高了治疗效果，还扩大了蛋白降解应用的范围。尽管具有巨大的潜力，但 TPD 在药物的性质及其合理设计方面面临挑战。本综述从 TPD 的最初概念化到实际应用，全面探讨了 TPD 的机制和临床进展，特别关注了蛋白水解靶向嵌合体和分子胶。此外，本综述还深入探讨了旨在解决这些挑战和提高治疗效果的新兴技术和方法。我们还讨论了重大临床试验，并强调了 TPD 药物相关的有前途的治疗结果，表明它们有潜力改变治疗格局。此外，本综述还考虑了将 TPD 与其他疗法联合使用以提高整体治疗效果并克服耐药性的好处。还探讨了 TPD 应用的未来方向，对进一步创新持乐观态度。通过全面概述当前的创新和面临的挑战，本综述评估了 TPD 在药物开发和疾病管理方面的变革潜力，为医学治疗的新时代奠定了基础。
