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Angew Chem Int Ed Engl. 2016 Feb 5;55(6):1966-73. doi: 10.1002/anie.201507978. Epub 2016 Jan 12.

Small-Molecule PROTACS: New Approaches to Protein Degradation.

Author information

1
Departments of Chemistry; Molecular, Cellular & Developmental Biology, Pharmacology, Yale University, New Haven, CT, 06511, USA.
2
Departments of Chemistry; Molecular, Cellular & Developmental Biology, Pharmacology, Yale University, New Haven, CT, 06511, USA. craig.crews@yale.edu.

Abstract

The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.

KEYWORDS:

E3 ligases; PROTACs; drug design; inhibitors; protein degradation

PMID:
26756721
DOI:
10.1002/anie.201507978
[Indexed for MEDLINE]

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