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

Dazhao Mi; Yuzhan Li; Haijun Gu; Yan Li; Yihua Chen

doi:10.1016/j.ejmech.2023.115444

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

Eur J Med Chem. 2023 Aug 5:256:115444. doi: 10.1016/j.ejmech.2023.115444. Epub 2023 May 8.

Authors

Dazhao Mi¹, Yuzhan Li¹, Haijun Gu¹, Yan Li¹, Yihua Chen²

Affiliations

¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
² Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: yhchen@bio.ecnu.edu.cn.

PMID: 37178483
DOI: 10.1016/j.ejmech.2023.115444

Abstract

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.

Keywords: CRBN; Degradation; E3 ligase; PROTACs; Small molecule; VHL.

Publication types

Review

MeSH terms

Drug Discovery*
Ligands
Proteolysis
Ubiquitin-Protein Ligases* / metabolism

Substances

Ligands
Ubiquitin-Protein Ligases