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Angew Chem Int Ed Engl. 2014 Feb 24;53(9):2312-30. doi: 10.1002/anie.201307761. Epub 2014 Jan 23.

Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system.

Author information

1
Departments of Chemistry; Molecular, Cellular and Developmental Biology; and Pharmacology, Yale University, New Haven, CT 06511 (USA).

Abstract

Traditionally, biological probes and drugs have targeted the activities of proteins (such as enzymes and receptors) that can be readily controlled by small molecules. The remaining majority of the proteome has been deemed "undruggable". By using small-molecule modulators of the ubiquitin proteasome, protein levels, rather than protein activity, can be targeted instead, thus increasing the number of druggable targets. Whereas targeting of the proteasome itself can lead to a global increase in protein levels, the targeting of other components of the UPS (e.g., the E3 ubiquitin ligases) can lead to an increase in protein levels in a more targeted fashion. Alternatively, multiple strategies for inducing protein degradation with small-molecule probes are emerging. With the ability to induce and inhibit the degradation of targeted proteins, small-molecule modulators of the UPS have the potential to significantly expand the druggable portion of the proteome beyond traditional targets, such as enzymes and receptors.

KEYWORDS:

drug design; inhibitors; proteasome; protein degradation; ubiquitin

PMID:
24459094
PMCID:
PMC4348030
DOI:
10.1002/anie.201307761
[Indexed for MEDLINE]
Free PMC Article

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