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PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery
Author(s) -
Gu Shanshan,
Cui Danrui,
Chen Xiaoyu,
Xiong Xiufang,
Zhao Yongchao
Publication year - 2018
Publication title -
bioessays
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.175
H-Index - 184
eISSN - 1521-1878
pISSN - 0265-9247
DOI - 10.1002/bies.201700247
Subject(s) - ubiquitin ligase , drug discovery , protein degradation , ubiquitin , proteasome , proteolysis , computational biology , dna ligase , target protein , biology , chemistry , microbiology and biotechnology , bioinformatics , biochemistry , dna , enzyme , gene
Proteolysis‐targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero‐bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non‐enzymatic proteins, which are not limited to physiological substrates of the ubiquitin‐proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC‐based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery.