Protein Tyrosine Phosphatase 1B Inhibition: Opportunities and Challenges
Affiliation: Metabolic Disease Research, R4MC, AP10, Abbott Laboratories, Abbott Park, IL 60064-6098, USA.
Protein tyrosine phosphatase 1B (PTP1B) has been implicated as one of the key negative regulators of insulin and leptin signal transduction pathways. PTP1B deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than the wild-type control mice. Inhibiting PTP1B action using antisense oligonucleotides and small molecule inhibitors represents novel therapeutic approach for the treatment of insulin resistance, type II diabetes, and obesity. The rapid development of this field is evidenced by the increasing number of patents and publications in recent years. This review will highlight the recent advances in various approaches for attenuating PTP1B action, particularly small molecule PTP1B inhibitors, and the challenges associated with developing PTP1B inhibitors with drug like properties.
Keywords: insulin resistance, type II diabetes, obesity, protein tyrosine phosphatase, antisense oligonucleotide, phosphotyrosyl mimetics, structure-based drug design, cellular permeability, second phosphotyrosyl binding site
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