Nano Proteolysis Targeting Chimeras (PROTACs) with Anti-Hook Effect for Tumor Therapy

作者：Zhang, Ni-Yuan; Hou, Da-Yong; Hu, Xing-Jie; Liang, Jian-Xiao; Wang, Man-Di; Song, Zhang-Zhi; Yi, Li; Wang, Zhi-Jia; An, Hong-Wei^*; Xu, Wanhai^*; Wang, Hao^*

来源：Angewandte Chemie - International Edition, 2023, 62(37).

DOI：10.1002/anie.202308049

• Nanomedicine
• PROTACs
• Peptide
• Self-Assembly
• Tumor

Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post-translational protein degradation capabilities. However, off-target induced unintended tissue effects and intrinsic "hook effect" hinder PROTAC biotechnology to be maturely developed. Herein, an intracellular fabricated nano proteolysis targeting chimeras (Nano-PROTACs) modality with a center-spoke degradation network for achieving efficient dose-dependent protein degradation in tumor is reported. The PROTAC precursors are triggered by higher GSH concentrations inside tumor cells, which subsequently in situ self-assemble into Nano-PROTACs through intermolecular hydrogen bond interactions. The fibrous Nano-PROTACs can form effective polynary complexes and E3 ligases degradation network with multi-binding sites, achieving dose-dependent protein degradation with "anti-hook effect". The generality and efficacy of Nano-PROTACs are validated by degrading variable protein of interest (POI) such as epidermal growth factor receptor (EGFR) and androgen receptor (AR) in a wide-range dose-dependent manner with a 95 % degradation rate and long-lasting potency up to 72 h in vitro. Significantly, Nano-PROTACs achieve in vivo dose-dependent protein degradation up to 79 % and tumor growth inhibition in A549 and LNCap xenograft mice models, respectively. Taking advantages of in situ self-assembly strategy, the Nano-PROTACs provide a generalizable platform to promote precise clinical translational application of PROTAC.

• 单位
  中国科学院研究生院; 国家纳米科学中心; 哈尔滨医科大学; 郑州大学