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Targeted degradation of PCNA outperforms stoichiometric inhibition to result in programed cell death

Shih Chieh Chang1, Pooja Gopal1, Shuhui Lim1

  • 1Quantitative Biosciences, MSD, Singapore 119077, Singapore.

Cell Chemical Biology
|November 1, 2022
PubMed

Insights

Biodegraders offer a superior therapeutic approach by degrading target proteins like PCNA, unlike traditional inhibitors. This targeted protein degradation demonstrated potent anti-cancer effects and complete tumor inhibition in vivo.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biotechnology

Background:

  • Biodegraders are novel protein degradation constructs.
  • Proliferating cell nuclear antigen (PCNA) is a key oncology target.
  • Targeted protein degradation offers a potential therapeutic advantage over inhibition.

Purpose of the Study:

  • To investigate the efficacy of Con1-SPOP, a biodegrader targeting PCNA.
  • To compare the effects of biodegrader-mediated PCNA degradation with stoichiometric inhibition.
  • To evaluate the in vivo therapeutic potential of biodegraders.

Main Methods:

  • Utilized Con1-SPOP, a biodegrader targeting PCNA.
  • Compared Con1-SPOP with its stoichiometric inhibitor (Con1-SPOPmut).
  • Assessed anti-proliferative effects, DNA damage, apoptosis, and necrosis.
  • Employed proteomics to analyze downstream effects of PCNA degradation.
  • Evaluated in vivo tumor growth inhibition and mRNA delivery via lipid nanoparticles (LNPs).

Main Results:

  • Con1-SPOP exhibited superior anti-proliferative effects compared to Con1-SPOPmut.
  • PCNA degradation induced DNA damage, apoptosis, and necrosis.
  • Proteomics revealed impaired mitotic division and mitochondria dysfunction due to PCNA degradation.
  • Doxycycline-induced Con1-SPOP achieved complete tumor growth inhibition in vivo.
  • LNP-delivered mRNA encoding Con1-SPOP rapidly depleted endogenous PCNA with nanomolar potency.

Conclusions:

  • Biodegraders represent a powerful tool for biological research and therapy.
  • Targeted protein degradation is a more efficacious strategy than stoichiometric inhibition.
  • Biodegraders hold promise as a future therapeutic modality upon optimization of in vivo delivery.
Keywords:
Con1PCNASPOPbiodegradertargeted degradationubiquitin-proteasome

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