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

Taoda Shi, E. M. Kithsiri Wijeratne, Cristian Solano, Andrew J. Ambrose, Alison B. Ross, Charles Norwood, Charles K. Orido, Tigran Grigoryan, Joseph Tillotson, Minjin Kang, Gang Luo, Bradley M. Keegan, Wenhao Hu, Brian S.J. Blagg, Donna D. Zhang, A. A. Leslie Gunatilaka, Eli Chapman

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3225-3231
Number of pages7
Issue number30
StatePublished - Jul 30 2019

ASJC Scopus subject areas

  • Biochemistry


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