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<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> Graphical abstract <p>Novel PROTACs alleviate the low permeability of traditional PROTACs and promote the stable ternary complex formation, thereby enhancing degradation efficacy.</p> <p></p>

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Unraveling the secrets of novel PROTACs to improve degradation efficacy

  • 期刊论文

  • 发表日期：

    2025年7月5日

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

摘要

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.

Graphical abstract

Novel PROTACs alleviate the low permeability of traditional PROTACs and promote the stable ternary complex formation, thereby enhancing degradation efficacy.