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 ...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^(P)),into the repertoire of E3 ligases for targeted protein degradation(TPD).Specifically,we rationally designed a Parkin-activating ligand Ub^(P)-M based on Ub^(P)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^(P)-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.展开更多
基金supported by the National Key R&D Program of China(2023YFC2306500 for Yuanyuan Yu)the National Natural Science Foundation of China(22207070,22477076 for Yuanyuan Yu,22477075 for Honggang Hu,22407085 for Qingyun Zheng,22307071 for Qian Qu)for the support+7 种基金supported by the Foundation of the National Facility for Translational Medicine(Shanghai)(TMSK-2024-110)supported by the Shanghai Jiao Tong University 2030 InitiativeChenguang Program of Shanghai Education Development FoundationShanghai Municipal Education Commissionsupported by the Shanghai Rising-Star Program(22QA1404900)the Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University(21TQ1400224)the Fundamental Research Funds for the Central Universitythe Shanghai Jiao Tong University 2030 Initiative。
文摘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^(P)),into the repertoire of E3 ligases for targeted protein degradation(TPD).Specifically,we rationally designed a Parkin-activating ligand Ub^(P)-M based on Ub^(P)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^(P)-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.
