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Targeted Protein Degradation: Current and Emerging Approaches for E3 Ligase Deconvolution.

Yufeng XiaoYaxia YuanYi LiuZongtao LinGuangrong ZhengDaohong ZhouDongwen Lv
Published in: Journal of medicinal chemistry (2024)
Targeted protein degradation (TPD), including the use of proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) to degrade proteins, is an emerging strategy to develop novel therapies for cancer and beyond. PROTACs or MGDs function by inducing the proximity between an E3 ligase and a protein of interest (POI), leading to ubiquitination and consequent proteasomal degradation of the POI. Notably, one major issue in TPD is the lack of ligandable E3 ligases, as current studies predominantly use CUL4 CRBN and CUL2 VHL . The TPD community is seeking to expand the landscape of ligandable E3 ligases, but most discoveries rely on phenotypic screens or serendipity, necessitating systematic target deconvolution. Here, we examine and discuss both current and emerging E3 ligase deconvolution approaches for degraders discovered from phenotypic screens or monovalent glue chemistry campaigns, highlighting future prospects for identifying more ligandable E3 ligases.
Keyphrases
  • cancer therapy
  • protein protein
  • amino acid
  • healthcare
  • high throughput
  • genome wide
  • binding protein
  • current status
  • gene expression
  • papillary thyroid
  • dna methylation
  • squamous cell carcinoma
  • lymph node metastasis