Protein Tyrosine Phosphatase 1B Inhibitors: Catechols

Abstract

As most intracellular signaling takes place via cascades of phosphorylation and dephosphorylation of tyrosines, protein tyrosine phosphatases have emerged as new and promising targets. Among them, protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by dephosphorylation of key tyrosine residues within the regulatory domain of the β-subunit of the insulin receptor, thereby attenuating receptor tyrosine kinase activity. Echelby et al. have demonstrated that PTP-1B knock-out mice fed with high-fat diet showed enhanced insulin sensitivity without any adverse symptoms. Thus, PTP-1B inhibitor could potentially ameliorate insulin resistance and normalize plasma glucose and insulin without inducing hypoglycemia. Recently, small molecule inhibitors of PTP-1B as well as peptide mimetics were reported in literatures. They included catechol A, o-quinones B-D, and carboxylic acids E-G. One of the inhibitors, Ertiprotafib (G) went to clinical trial, but was discontinued in Phase II due to insufficient efficacy and dose-dependent side effects. Some catechol derivatives were discovered as hits from high-throughput screening of the library of Korea Chemical Bank. As phenolic compounds with anti-oxidant activities are known to be beneficial in the treatment of diabetes and related disorders, and catechol A and similar compounds