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

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.

Automated summary

Reported here is an intracellular fabricated Nano-PROTACs modality with a center-spoke degradation network, which achieves efficient dose-dependent protein degradation in tumor. Nano-PROTACs are self-assembled by intermolecular hydrogen bond interactions triggered by higher GSH concentrations inside tumor cells, forming fibrous structures that can form effective polynary complexes and E3 ligases degradation network. Nano-PROTACs demonstrate dose-dependent protein degradation of variable proteins of interest (POI) in vitro, with a degradation rate of 95% and long-lasting potency up to 72 h. In vivo, Nano-PROTACs achieve dose-dependent protein degradation up to 79% and tumor growth inhibition in xenograft mouse models.