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<p>Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.</p>

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Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月28日

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  • Mireia Casasampere,
  • Hector Carneros,
  • Tania Roda,
  • Alice Zuin,
  • Núria Gallisà-Suñé,
  • Alba González-Artero,
  • Bernat Coll-Martínez,
  • José Luis Abad,
  • Abdulateef Alqahtani,
  • Josefina Casas,
  • Patricia Fernández-Nogueira,
  • Antonio Delgado,
  • Jordi Bujons,
  • Gemma Fabriàs,
  • Bernat Crosas

摘要

Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.