Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022

Author:

Tamatam Rekha12,Shin Dongyun12

Affiliation:

1. College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea

2. Gachon Pharmaceutical Research Institute, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea

Abstract

Targeted protein degradation (TPD) is a promising therapeutic modality that has garnered attention in academic, industrial, and pharmaceutical research for treating diseases such as cancer, neurodegenerative disorders, inflammation, and viral infections. In this context, proteolysis-targeting chimeras (PROTACs) present a reliable technology for degrading disease-causing proteins. PROTACs complement small-molecule inhibitors, which primarily rely on direct protein regulation. From concept-to-clinic, PROTACs have evolved from cell impermeable peptide molecules to orally bioavailable drugs. Despite their potential in medicinal chemistry, certain aspects regarding PROTACs remain unclear. The clinical significance of PROTACs is primarily limited owing to their lack of selectivity and drug-like properties. This review focused on recently reported PROTAC strategies, particularly in 2022. It aimed to address and overcome the challenges posed by classical PROTACs by correlating them with emerging approaches with improved selectivity and controllability, cell permeability, linker flexibility, druggability, and PROTAC-based approaches, developed in 2022. Furthermore, recently reported PROTAC-based approaches are discussed, highlighting each of their advantages and limitations. We predict that several improved PROTAC molecules will be accessible for treating patients exhibiting various conditions, including cancer, neurodegenerative disorders, inflammation, and viral infections.

Funder

National Research Foundation of Korea

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference71 articles.

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