Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design

Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overco...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2023-08, Vol.256, p.115444-115444, Article 115444
Main Authors: Mi, Dazhao, Li, Yuzhan, Gu, Haijun, Li, Yan, Chen, Yihua
Format: Article
Language:English
Subjects:
CRBN
Degradation
Drug Discovery
E3 ligase
Ligands
PROTACs
Proteolysis
Small molecule
Ubiquitin-Protein Ligases - metabolism
VHL
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Summary:Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed. [Display omitted] • •E3 ligands are crucial module for PROTACs design.• •Summary of the current E3 ligases and corresponding ligands.• •Description of the significance and prospects for developing novel E3 ligases.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2023.115444