Design and pharmaceutical applications of proteolysis-targeting chimeric molecules

Yuqing Liang; Kutty Selva Nandakumar; Kui Cheng

doi:10.1016/j.bcp.2020.114211

Design and pharmaceutical applications of proteolysis-targeting chimeric molecules

Biochem Pharmacol. 2020 Dec:182:114211. doi: 10.1016/j.bcp.2020.114211. Epub 2020 Aug 29.

Authors

Yuqing Liang¹, Kutty Selva Nandakumar¹, Kui Cheng²

Affiliations

¹ Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
² Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: Chengk@smu.edu.cn.

PMID: 32866456
DOI: 10.1016/j.bcp.2020.114211

Abstract

Proteolysis-targeting chimeras (PROTACs), the hetero-bifunctional compounds containing a specific ligand to bind the target protein, a suitable linker, and an E3 ubiquitin ligase substrate, are being developed for therapeutic applications. PROTACs hijack the catalytic activity of ubiquitin E3 ligases to mediate proteasome dependent degradation of selected protein of interest (POI), by bringing the ligase and POI into close spatial proximity and initiating the poly-ubiquitination process. Compared to the traditional small-molecule drugs, PROTACs reduce the problems of dosage, drug resistance, side effects and undruggable targets that could not be targeted pharmacologically. In this review, all the POIs, and peptide to small-molecule based PROTACs developed during the past two decades are summarized and directions for future development are discussed.

Keywords: Degradation; PROTACs; Small-molecule drug; Ubiquitination.

Publication types

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

MeSH terms

Animals
Drug Delivery Systems / methods*
Drug Delivery Systems / trends
Drug Design*
Drug Discovery / methods
Drug Discovery / trends
Humans
Oligopeptides / administration & dosage
Oligopeptides / chemical synthesis*
Protein Structure, Tertiary
Proteolysis / drug effects*

Substances

Oligopeptides
PROTAC-4