An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

A library
of natural products and their derivatives was screened
for inhibition of protein tyrosine phosphatase (PTP) 1B, which is
a validated drug target for the treatment of obesity and type II diabetes.
Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold
derived by treating radicicol (1) with hydrazine. This
nitrogen-atom augmented radicicol derivative was found to be PTP1B
selective relative to other highly homologous nonreceptor PTPs. Biochemical
evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar Ki. Cellular analyses using C2C12 myoblasts indicated
that 2 restored insulin signaling and increased glucose
uptake.