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Crit Rev Biochem Mol Biol. 2014 Mar-Apr;49(2):102-15. doi: 10.3109/10409238.2013.875513. Epub 2014 Feb 25.

Bivalent inhibitors of protein kinases.

Author information

1
Department of Chemistry, University of Washington , Seattle, WA , USA.

Abstract

Protein kinases are key players in a large number of cellular signaling pathways. Dysregulated kinase activity has been implicated in a number of diseases, and members of this enzyme family are of therapeutic interest. However, due to the fact that most inhibitors interact with the highly conserved ATP-binding sites of kinases, it is a significant challenge to develop pharmacological agents that target only one of the greater than 500 kinases present in humans. A potential solution to this problem is the development of bisubstrate and bivalent kinase inhibitors, in which an active site-directed moiety is tethered to another ligand that targets a location outside of the ATP-binding cleft. Because kinase signaling specificity is modulated by regions outside of the ATP-binding site, strategies that exploit these interactions have the potential to provide reagents with high target selectivity. This review highlights examples of kinase interaction sites that can potentially be exploited by bisubstrate and bivalent inhibitors. Furthermore, an overview of efforts to target these interactions with bisubstrate and bivalent inhibitors is provided. Finally, several examples of the successful application of these reagents in a cellular setting are described.

PMID:
24564382
PMCID:
PMC4627631
DOI:
10.3109/10409238.2013.875513
[Indexed for MEDLINE]
Free PMC Article

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