Protein tyrosine phosphatases (PTPs) comprise a large family of proteins that work in tandem with protein tyrosine kinases (PTKs) to control multiple signaling pathways. PTP1B is a negative regulator of the insulin and leptin signaling pathways and inhibitors of this enzyme could be used in the treatment of type II diabetes.  However, traditional reversible inhibitors of this PTP1B suffer from lack of selectivity and/or poor bioavailability. Here we describe our efforts to pursue a novel exo-affinity labeling strategy for inactivation of PTP1B. Toward this end, we have synthesized compounds consisting of a known phosphotyrosine isostere combined with a biocompatible electrophile. We will present evidence that these agents inactivate PTP1B via a mechanism involving noncovalent association of the phosphotyrosine isostere with the active site, followed by covalent modification of residues outside the enzyme active site. Exploiting the covalent reactivity of protein functional groups outside the enzyme's catalytic pocket represents a new approach for the selective knockdown of PTP activity.

Inactivation of protein tyrosine phosphatase 1B by exo-affinity labeling agents

246th National Meeting (2013)

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