{"title":"将靶向蛋白降解的经验教训推广到其他近端诱导药物中","authors":"Georg E. Winter","doi":"10.1021/acschembio.4c00191","DOIUrl":null,"url":null,"abstract":"Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule “degraders” that induce proximity of a component of an E3 ubiquitin ligase complex and a target protein to induce target ubiquitination and subsequent proteasomal degradation. Essentially, degraders thus expand the function of E3 ligases, allowing them to degrade proteins they would not recognize in the absence of the small molecule. Over the past decade, insights gained from identifying, designing, and characterizing various degraders have significantly enhanced our understanding of TPD mechanisms, precipitating in rational degrader discovery strategies. In this Account, I aim to explore how these insights can be extrapolated to anticipate both opportunities and challenges of utilizing the overarching concept of proximity-inducing pharmacology to manipulate other cellular circuits for the dissection of biological mechanisms and for therapeutic purposes.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs\",\"authors\":\"Georg E. Winter\",\"doi\":\"10.1021/acschembio.4c00191\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule “degraders” that induce proximity of a component of an E3 ubiquitin ligase complex and a target protein to induce target ubiquitination and subsequent proteasomal degradation. Essentially, degraders thus expand the function of E3 ligases, allowing them to degrade proteins they would not recognize in the absence of the small molecule. Over the past decade, insights gained from identifying, designing, and characterizing various degraders have significantly enhanced our understanding of TPD mechanisms, precipitating in rational degrader discovery strategies. In this Account, I aim to explore how these insights can be extrapolated to anticipate both opportunities and challenges of utilizing the overarching concept of proximity-inducing pharmacology to manipulate other cellular circuits for the dissection of biological mechanisms and for therapeutic purposes.\",\"PeriodicalId\":11,\"journal\":{\"name\":\"ACS Chemical Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Chemical Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1021/acschembio.4c00191\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1021/acschembio.4c00191","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs
Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule “degraders” that induce proximity of a component of an E3 ubiquitin ligase complex and a target protein to induce target ubiquitination and subsequent proteasomal degradation. Essentially, degraders thus expand the function of E3 ligases, allowing them to degrade proteins they would not recognize in the absence of the small molecule. Over the past decade, insights gained from identifying, designing, and characterizing various degraders have significantly enhanced our understanding of TPD mechanisms, precipitating in rational degrader discovery strategies. In this Account, I aim to explore how these insights can be extrapolated to anticipate both opportunities and challenges of utilizing the overarching concept of proximity-inducing pharmacology to manipulate other cellular circuits for the dissection of biological mechanisms and for therapeutic purposes.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.