Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery

Jia-Yue Xi; Ru-Yue Zhang; Ke Chen; Lin Yao; Mu-Qiong Li; Ru Jiang; Xiao-Ye Li; Li Fan

doi:10.1016/j.bioorg.2022.105848

Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery

Bioorg Chem. 2022 Aug;125:105848. doi: 10.1016/j.bioorg.2022.105848. Epub 2022 May 5.

Authors

Jia-Yue Xi¹, Ru-Yue Zhang¹, Ke Chen¹, Lin Yao¹, Mu-Qiong Li¹, Ru Jiang¹, Xiao-Ye Li¹, Li Fan²

Affiliations

¹ Department of Pharmaceutical Chemistry and Analysis, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
² Department of Pharmaceutical Chemistry and Analysis, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: xxfanny@fmmu.edu.cn.

PMID: 35533582
DOI: 10.1016/j.bioorg.2022.105848

Abstract

Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.

Keywords: Drug discovery; PROTACs; Small inhibitors; Target protein degradation; Undruggable target.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Drug Discovery*
Ligands
Proteolysis*
Ubiquitin-Protein Ligases*

Substances

Ligands
Ubiquitin-Protein Ligases