Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

  • J Med Chem. 2023 Apr 24. doi: 10.1021/acs.jmedchem.3c00013.
Zhihang Wang  1  2 ,  Mixiao Tan  3 ,  Wen Su  1 ,  Wenping Huang  1  2 ,  Jie Zhang  1  2 ,  Fuhao Jia  1  2 ,  Guoliang Cao  1 ,  Xinyang Liu  1 ,  Haohao Song  1 ,  Haitao Ran  3 ,  Guangjun Nie  1 ,  Hai Wang  1  2
Affiliations
  • 1. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China.
PMID: 37092695 DOI: 10.1021/acs.jmedchem.3c00013
Abstract

Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and Cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and Proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.

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