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Covalent inhibition of protein tyrosine phosphatases

Abstract

Protein tyrosine phosphatases (PTPs) are a large family of 107 signaling enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in a target protein. The phosphorylation status of tyrosine residues on proteins serve as a ubiquitous mechanism for cellular signal transduction. Aberrant function of PTPs can lead to many human diseases, such as diabetes, obesity, cancer, and autoimmune diseases. As the number of disease relevant PTPs increases, there is urgency in developing highly potent inhibitors that are selective towards specific PTPs. Most of current efforts have been devoted to the development of active site-directed and reversible inhibitors for the PTPs. This review summarizes the recent progress made in the field of covalent inhibitors to target the PTPs. Here we discuss the in vivo and in vitro inactivation of various PTPs by small molecules containing electrophiles, such as Michael acceptors, α-halo ketones, epoxides, and isothiocyanates, etc. as well as oxidizing agents. We also suggest potential strategies to transform these electrophiles into isozyme selective covalent PTP inhibitors.

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Publication details

The article was received on 13 Mar 2017, accepted on 09 May 2017 and first published on 10 May 2017


Article type: Review Article
DOI: 10.1039/C7MB00151G
Citation: Mol. BioSyst., 2017, Accepted Manuscript
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    Covalent inhibition of protein tyrosine phosphatases

    K. V. Ruddraraju and Z. Zhang, Mol. BioSyst., 2017, Accepted Manuscript , DOI: 10.1039/C7MB00151G

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