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<p>Proteolysis targeting chimeras (PROTACs) have been considered a promising therapeutic strategy, but their application is restricted by the limited number of available E3 ligases. Here, we expanded Parkin, an autoinhibitory E3 whose activity can be triggered by binding to its activating ligand, phosphorylated ubiquitin (Ub<sup>P</sup>), into the repertoire of E3 ligases for targeted protein degradation (TPD). Specifically, we rationally designed a Parkin-activating ligand Ub<sup>P</sup>-M based on Ub<sup>P</sup> and conjugated it with small-molecule binders against target proteins such as Brd4 and SF3B1 using total chemical synthesis. These degraders successfully induced ubiquitination and degradation of target proteins. Notably, conjugating small-molecule binders of Brd4 and SF3B1 together to Ub<sup>P</sup>-M simultaneously targets both proteins for degradation. As a proof-of-concept, our studies demonstrate the potential of Parkin as a potential E3 ligase for PROTACs, providing a new framework for developing targeted degraders via dynamic activation mechanisms.</p>

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Chemically synthesized phosphorylated ubiquitin unlocks parkin for activation-controlled PROTAC platforms

  • 期刊论文

  • 发表日期：

    2025年7月29日

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  • Fangdan Chen,
  • Qing Zhan,
  • Qian Qu,
  • Siyi Cui,
  • Yicheng Weng,
  • Man Pan,
  • Qingyun Zheng,
  • Honggang Hu,
  • Yuanyuan Yu

摘要

Proteolysis targeting chimeras (PROTACs) have been considered a promising therapeutic strategy, but their application is restricted by the limited number of available E3 ligases. Here, we expanded Parkin, an autoinhibitory E3 whose activity can be triggered by binding to its activating ligand, phosphorylated ubiquitin (UbP), into the repertoire of E3 ligases for targeted protein degradation (TPD). Specifically, we rationally designed a Parkin-activating ligand UbP-M based on UbP and conjugated it with small-molecule binders against target proteins such as Brd4 and SF3B1 using total chemical synthesis. These degraders successfully induced ubiquitination and degradation of target proteins. Notably, conjugating small-molecule binders of Brd4 and SF3B1 together to UbP-M simultaneously targets both proteins for degradation. As a proof-of-concept, our studies demonstrate the potential of Parkin as a potential E3 ligase for PROTACs, providing a new framework for developing targeted degraders via dynamic activation mechanisms.