Targeted protein degradation: advances in drug discovery and clinical practice
靶向蛋白降解：在药物发现和临床实践中的进展
摘要 (Abstract)
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
实验设计与方法 (Experimental Design & Methods)
采用结构生物学、计算机模拟和实验验证相结合的方法，系统分析蛋白质结构和功能关系。通过分子对接、动力学模拟等技术预测药物-靶点相互作用。
实验结果 (Experimental Results)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
数据汇总 (Data Summary)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
结论 (Conclusions)
基于蛋白质的药物研发策略为创新药物开发提供了新方向。
实践意义 (Practical Significance)
对推动靶向药物研发和精准医疗发展具有重要科学价值。