An isoform-selective PTP1B inhibitor derived from nitrogen-atom augmentation of radicicol.

08:00 EDT 12th July 2019 | BioPortfolio

Summary of "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 non-receptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a sub-µM Ki. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signalling and increased glucose uptake.


Journal Details

This article was published in the following journal.

Name: Biochemistry
ISSN: 1520-4995


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Medical and Biotech [MESH] Definitions

5'-Adenylic acid, monoanhydride with imidodiphosphoric acid. An analog of ATP, in which the oxygen atom bridging the beta to the gamma phosphate is replaced by a nitrogen atom. It is a potent competitive inhibitor of soluble and membrane-bound mitochondrial ATPase and also inhibits ATP-dependent reactions of oxidative phosphorylation.

Tetrahydrofolates which are substituted by a formyl group at either the nitrogen atom in the 5 position or the nitrogen atom in the 10 position. N(5)-Formyltetrahydrofolate is leukovorin (citrovorum factor) while N(10)-formyltetrahydrofolate is an active coenzyme which functions as a carrier of the formyl group in a number of enzymatic reactions.

Organic compounds containing a carbon-nitrogen double bond where a NITROGEN atom can be attached to HYDROGEN or an alkyl or aryl group.

A non-hydrolyzable analog of GTP, in which the oxygen atom bridging the beta to the gamma phosphate is replaced by a nitrogen atom. It binds tightly to G-protein in the presence of Mg2+. The nucleotide is a potent stimulator of adenylate cyclase.

Liquid perfluorinated carbon compounds which may or may not contain a hetero atom such as nitrogen, oxygen or sulfur, but do not contain another halogen or hydrogen atom. This concept includes fluorocarbon emulsions and fluorocarbon blood substitutes.

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