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

• Published in: Biochemistry (Easton) 2019-07, Vol.58 (30), p.3225-3231
• Main Authors: Shi, Taoda, Wijeratne, E. M. Kithsiri, Solano, Cristian, Ambrose, Andrew J, Ross, Alison B, Norwood, Charles, Orido, Charles K, Grigoryan, Tigran, Tillotson, Joseph, Kang, Minjin, Luo, Gang, Keegan, Bradley M, Hu, Wenhao, Blagg, Brian S. J, Zhang, Donna D, Gunatilaka, A. A. Leslie, Chapman, Eli
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Macrolides - chemistry; Macrolides - metabolism; Mice; Nitrogen - chemistry; Nitrogen - metabolism; Protein Binding - physiology; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.9b00499

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 K i. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.