Work

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

Year: 2019

Type: article

Abstract: 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.

Source: Biochemistry

DOI: 10.1021/acs.biochem.9b00499

Authors: 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

Institutions: University of Arizona, East China Normal University, University of Notre Dame, Sun Yat-sen University

Language: English

Topic: Protein Tyrosine Phosphatases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: China Scholarship Council, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences

Awards: Diverse Molecular Libraries from Unique Endosymbiotic Fungi, Chemistry-Biology Interface Training Program, G4007902679, Anticancer Agents from Plant- and Lichen-Associated Fungi of the Sonoran Desert, G5617201294, G5871088526, Training in Environmental Toxicology of Human Disease

OpenAlex ID: W2958552573

FWCI: 0.574

Cites: 56

Cited by: 8

Related to: 10