Targeted protein degradation:advances in drug discovery and clinical practice

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外文摘要：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.

作者：

Guangcai Zhong、Xiaoyu Chang、Weilin Xie、Xiangxiang Zhou

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作者单位：

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

School of Pharmaceutical Sciences,Pingyuan Laboratory,Zhengzhou University,Zhengzhou 450001,China

institute of Materia Medica,Shandong First Medical University & Shandong Academy of Medical Sciences,Jinan,Shandong 250117,China

Department of Hematology,Shandong Provincial Hospital,Shandong University,Jinan,Shandong 250021,China

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出版年：

2024

DOI：

10.1038/s41392-024-02004-x

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(12)