An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol
| Autor: | Bradley M Keegan, Eli Chapman, Cristian Solano, A. A. Leslie Gunatilaka, Charles K. Orido, Tigran Grigoryan, Taoda Shi, E. M. Kithsiri Wijeratne, Donna D. Zhang, Joseph Tillotson, Wenhao Hu, Alison B. Ross, Gang Luo, Andrew J. Ambrose, Brian S. J. Blagg, MinJin Kang, Charles Norwood |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
Protein Tyrosine Phosphatase Non-Receptor Type 1 biology Chemistry Nitrogen Glucose uptake Mutagenesis Allosteric regulation Protein tyrosine phosphatase Biochemistry Article Radicicol Protein Structure Tertiary chemistry.chemical_compound Insulin receptor Mice biology.protein Animals Protein Isoforms Macrolides Enzyme Inhibitors C2C12 Protein Binding |
| Zdroj: | Biochemistry |
| Popis: | 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 pyrrolopyrazoloisoquino-lone 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. |
| Databáze: | OpenAIRE |
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