Journal
FUTURE MEDICINAL CHEMISTRY
Volume 14, Issue 19, Pages 1403-1416Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2022-0149
Keywords
cereblon; clinical progression; CRBN; E3 ligase; PROTAC; protein degradation; ubiquitination
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Funding
- National Institutes of Health, USA [R01 HL144125, R01 HL147662]
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Protease-targeted chimeras (PROTACs) are a novel therapeutic approach that utilizes the ubiquitin-proteasome system for targeted protein degradation. PROTACs based on small-molecule inhibitors have several advantages and cereblon-based PROTACs have promising clinical potential.
Protease-targeted chimeras (PROTACs) have been employed as a novel therapeutic approach, utilizing the ubiquitin-proteasome system for targeted protein degradation. PROTACs are heterobifunctional molecules consisting of an E3 ligase ligand and a small-molecule inhibitor for recruiting a protein of interest. After binding, PROTAC molecules recruit E3 ligase for ubiquitination of the protein of interest, which is followed by its proteasome-mediated degradation. PROTAC molecules have several advantages over traditional small-molecule inhibitors. A number of PROTAC molecules based on small-molecule inhibitors have been developed against various diseases, among which cereblon-based PROTAC molecules have received the greatest interest due to their promising clinical use. This article highlights the current trends in the discovery of cereblon-based PROTAC molecules along with their medicinal chemistry, clinical progression and future outlook in cancers, cardiovascular diseases and neurodegenerative disorders.
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