Unraveling the secrets of novel PROTACs to improve degradation efficacy.

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-07-05 DOI:10.1007/s11030-025-11273-9

Juan Huang, Xiaoyan Yang, Qiuqian Huang, Yangyang Gao, Pradeepa C G Bandaranayake, Wishwajith Kandegama, Charles R Ashby, Yawen Dong, Zhenchao Wang, Ge-Fei Hao

{"title":"Unraveling the secrets of novel PROTACs to improve degradation efficacy.","authors":"Juan Huang, Xiaoyan Yang, Qiuqian Huang, Yangyang Gao, Pradeepa C G Bandaranayake, Wishwajith Kandegama, Charles R Ashby, Yawen Dong, Zhenchao Wang, Ge-Fei Hao","doi":"10.1007/s11030-025-11273-9","DOIUrl":null,"url":null,"abstract":"<p><p>Proteolysis targeting chimera (PROTAC) represents a crucial approach for overcoming various limitations associated with traditional inhibitors, particularly in targeting \"undruggable\" proteins and overcoming the resistance of targets. The degradation efficiency of PROTAC is fundamental to its pharmacological activity. Improving PROTAC's degradation efficiency mainly focuses on small molecule design, exploring new mechanisms, and optimizing delivery strategies. However, there is a lack of comprehensive understanding regarding how novel PROTACs enhance degradation efficacy. Here, a comprehensive exploration of novel PROTACs has been conducted to reveal the mechanisms of enhanced degradation efficiency through an in-depth analysis of tremendous existing studies. Firstly, we describe the variables influencing PROTAC's degradation activity. Secondly, a complete analysis is launched between novel PROTACs and their traditional counterparts, elucidating the reasons for the improved degradation efficacy of newer forms. Finally, the successful cases are leveraged to verify the theoretical foundation underlying enhanced degradation efficacy. We believe this work is anticipated to offer new perspectives for the design and guide the creation of potent PROTACs.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11273-9","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

Proteolysis targeting chimera (PROTAC) represents a crucial approach for overcoming various limitations associated with traditional inhibitors, particularly in targeting "undruggable" proteins and overcoming the resistance of targets. The degradation efficiency of PROTAC is fundamental to its pharmacological activity. Improving PROTAC's degradation efficiency mainly focuses on small molecule design, exploring new mechanisms, and optimizing delivery strategies. However, there is a lack of comprehensive understanding regarding how novel PROTACs enhance degradation efficacy. Here, a comprehensive exploration of novel PROTACs has been conducted to reveal the mechanisms of enhanced degradation efficiency through an in-depth analysis of tremendous existing studies. Firstly, we describe the variables influencing PROTAC's degradation activity. Secondly, a complete analysis is launched between novel PROTACs and their traditional counterparts, elucidating the reasons for the improved degradation efficacy of newer forms. Finally, the successful cases are leveraged to verify the theoretical foundation underlying enhanced degradation efficacy. We believe this work is anticipated to offer new perspectives for the design and guide the creation of potent PROTACs.

查看原文本刊更多论文

揭示新型PROTACs提高降解效率的秘密。

蛋白水解靶向嵌合体（PROTAC）代表了克服传统抑制剂相关的各种局限性的关键方法，特别是在靶向“不可药物”蛋白质和克服靶标的耐药性方面。PROTAC的降解效率是其药理活性的基础。提高PROTAC的降解效率主要集中在小分子设计、探索新机制、优化给药策略等方面。然而，对于新型PROTACs如何提高降解效率，目前还缺乏全面的了解。本文通过对大量已有研究的深入分析，对新型PROTACs进行了全面的探索，揭示了其提高降解效率的机制。首先，我们描述了影响PROTAC降解活性的变量。其次，对新型PROTACs与传统PROTACs进行了全面分析，阐明了新型PROTACs降解效率提高的原因。最后，利用成功案例验证了提高降解效率的理论基础。我们相信这项工作有望为设计和指导创建有效的protac提供新的视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;