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Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system

Favour A Akinjiyan1, Seth Carbonneau1, Nathan T Ross1

  • 1Department of Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA.

Bioorganic & Medicinal Chemistry Letters
|September 16, 2017
PubMed

Insights

Targeting protein degradation pathways, including the ubiquitin proteasome system, offers therapeutic potential for diseases like cancer and neurodegeneration. This review covers novel screening methods and chemical biology tools for various enzymes and protein-protein interactions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Protein degradation is essential for maintaining cellular balance (proteostasis).
  • Polyubiquitin chain addition targets substrates for degradation by the 26S proteasome.
  • Dysregulation of the ubiquitin proteasome system is implicated in diseases like cancer and neurodegeneration.

Purpose of the Study:

  • To review novel screening methods and chemical biology tools for targeting the ubiquitin proteasome system.
  • To discuss therapeutic strategies focusing on enzymes and protein-protein interactions within this pathway.

Main Methods:

  • Review of recent literature on chemical biology tools.
  • Discussion of screening methods for enzyme and interaction targets.
  • Focus on targeting E1, E2, deubiquitinating enzymes, E3 ligase-substrate interactions, and the proteasome.

Main Results:

  • Emerging chemical biology tools and screening methods offer new ways to modulate protein degradation.
  • Targeting specific enzymes (E1, E2, DUBs) and interactions (E3 ligase-substrate) shows therapeutic promise.
  • Direct proteasome targeting strategies are also advancing.

Conclusions:

  • The ubiquitin proteasome system represents a rich target for therapeutic intervention.
  • Novel chemical biology approaches are expanding the possibilities for drug development in oncology and neurology.
  • Further research into these tools and targets will drive innovation in treating proteostasis-related diseases.
Keywords:
Drug discoveryHigh-throughputMolecular glueProteasomeProtein degradationUbiquitin

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