{"title":"靶向蛋白降解中的分子胶和PROTACs:机制、进展和治疗潜力","authors":"Omar Eladl","doi":"10.1016/j.bcp.2025.117297","DOIUrl":null,"url":null,"abstract":"<div><div>Targeted protein degradation (TPD) is a transformative approach to drug discovery that enables the modulation of proteins previously considered “undruggable.” Unlike traditional inhibitors, which transiently suppress protein activity, TPD harnesses the ubiquitin–proteasome system to selectively eliminate specific proteins and thereby fully abolish their activities. Two prominent approaches within TPD, Molecular Glues and PROteolysis TArgeting Chimeras (PROTACs), differ in both mechanism and therapeutic application.</div><div>Molecular Glues are small molecules with low molecular weight that act as a molecular bridge, facilitating interaction between a target protein and an E3 ubiquitin ligase to enable degradation without requiring classical binding pockets. PROTACs are heterobifunctional small molecules that simultaneously engage a target protein and an E3 ligase to induce selective degradation through a catalytic mechanism. Both strategies have vastly expanded the druggable proteome and hold great promise for therapeutic interventions.</div><div>This review provides a comparative overview of Molecular Glues and PROTACs, including their mechanisms, design principles, and therapeutic applications. We highlight their physicochemical properties, advantages, and limitations, as well as recent advances that are fueling the discovery of novel degraders. Through clinical advancements and case studies, we examine how these modalities are reshaping drug discovery and enabling new treatments for a variety of diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117297"},"PeriodicalIF":5.6000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular glues and PROTACs in targeted protein degradation: mechanisms, advances, and therapeutic potential\",\"authors\":\"Omar Eladl\",\"doi\":\"10.1016/j.bcp.2025.117297\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Targeted protein degradation (TPD) is a transformative approach to drug discovery that enables the modulation of proteins previously considered “undruggable.” Unlike traditional inhibitors, which transiently suppress protein activity, TPD harnesses the ubiquitin–proteasome system to selectively eliminate specific proteins and thereby fully abolish their activities. Two prominent approaches within TPD, Molecular Glues and PROteolysis TArgeting Chimeras (PROTACs), differ in both mechanism and therapeutic application.</div><div>Molecular Glues are small molecules with low molecular weight that act as a molecular bridge, facilitating interaction between a target protein and an E3 ubiquitin ligase to enable degradation without requiring classical binding pockets. PROTACs are heterobifunctional small molecules that simultaneously engage a target protein and an E3 ligase to induce selective degradation through a catalytic mechanism. Both strategies have vastly expanded the druggable proteome and hold great promise for therapeutic interventions.</div><div>This review provides a comparative overview of Molecular Glues and PROTACs, including their mechanisms, design principles, and therapeutic applications. We highlight their physicochemical properties, advantages, and limitations, as well as recent advances that are fueling the discovery of novel degraders. Through clinical advancements and case studies, we examine how these modalities are reshaping drug discovery and enabling new treatments for a variety of diseases.</div></div>\",\"PeriodicalId\":8806,\"journal\":{\"name\":\"Biochemical pharmacology\",\"volume\":\"242 \",\"pages\":\"Article 117297\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0006295225005623\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006295225005623","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Molecular glues and PROTACs in targeted protein degradation: mechanisms, advances, and therapeutic potential
Targeted protein degradation (TPD) is a transformative approach to drug discovery that enables the modulation of proteins previously considered “undruggable.” Unlike traditional inhibitors, which transiently suppress protein activity, TPD harnesses the ubiquitin–proteasome system to selectively eliminate specific proteins and thereby fully abolish their activities. Two prominent approaches within TPD, Molecular Glues and PROteolysis TArgeting Chimeras (PROTACs), differ in both mechanism and therapeutic application.
Molecular Glues are small molecules with low molecular weight that act as a molecular bridge, facilitating interaction between a target protein and an E3 ubiquitin ligase to enable degradation without requiring classical binding pockets. PROTACs are heterobifunctional small molecules that simultaneously engage a target protein and an E3 ligase to induce selective degradation through a catalytic mechanism. Both strategies have vastly expanded the druggable proteome and hold great promise for therapeutic interventions.
This review provides a comparative overview of Molecular Glues and PROTACs, including their mechanisms, design principles, and therapeutic applications. We highlight their physicochemical properties, advantages, and limitations, as well as recent advances that are fueling the discovery of novel degraders. Through clinical advancements and case studies, we examine how these modalities are reshaping drug discovery and enabling new treatments for a variety of diseases.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.