Novel approaches to targeted protein degradation technologies in drug discovery

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations


Introduction: Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein homeostasis mechanisms are exploited: the ubiquitin-proteasome system (UPS) and the lysosomal system. TPD technologies based on these two systems are progressing at an impressive pace. Areas Covered: This review focuses on the TPD strategies based on UPS and lysosomal system, mainly classified into three types: Molecular Glue (MG), PROteolysis Targeting Chimera (PROTAC), and lysosome-mediated TPD. Starting with a brief background introduction of each strategy, exciting examples and perspectives on these novel approaches are provided. Expert Opinion: MGs and PROTACs are two major UPS-based TPD strategies that have been extensively investigated in the past decade. Despite some clinical trials, several critical issues remain, among which is emphasized by the limitation of targets. Recently developed lysosomal system-based approaches provide alternative solutions for TPD beyond UPS’ capability. The newly emerging novel approaches may partially address issues that have long plagued researchers, such as low potency, poor cell permeability, on-/off-target toxicity, and delivery efficiency. Comprehensive considerations for the rational design of protein degraders and continuous efforts to seek effective solutions are imperative to advance these strategies into clinical medications.

Original languageEnglish (US)
Pages (from-to)467-483
Number of pages17
JournalExpert Opinion on Drug Discovery
Issue number4
StatePublished - Apr 2023


  • AuTophagosome-TEthering Compound (ATTEC)
  • AUtophagy-TArgeting Chimera (AUTAC)
  • AUTOphagy-TArgeting Chimera (AUTOTAC)
  • drug discovery
  • lysosomal system
  • LYsosome-TArgeting Chimera (LYTAC)
  • Molecular Glue (MG)
  • protein degraders
  • PROteolysis Targeting Chimera (PROTAC)
  • Target Protein Degradation (TPD)
  • Ubiquitin-Proteasome System (UPS)
  • Humans
  • Permeability
  • Drug Discovery
  • Proteolysis Targeting Chimera
  • Research Personnel
  • Proteolysis

ASJC Scopus subject areas

  • Drug Discovery


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