An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.
Taoda ShiE M Kithsiri WijeratneCristian SolanoAndrew J AmbroseAlison B RossCharles NorwoodCharles K OridoTigran GrigoryanJoseph TillotsonMinjin KangGang LuoBradley M KeeganWenhao HuBrian S J BlaggDonna D ZhangA A Leslie GunatilakaEli ChapmanPublished in: Biochemistry (2019)
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.
Keyphrases
- molecular docking
- type diabetes
- glycemic control
- molecular dynamics
- molecular dynamics simulations
- small molecule
- metabolic syndrome
- insulin resistance
- cardiovascular disease
- crispr cas
- weight loss
- dna damage
- high throughput
- blood glucose
- single cell
- emergency department
- lymph node
- body mass index
- fluorescent probe
- squamous cell carcinoma
- protein protein
- binding protein
- dna repair
- skeletal muscle
- adipose tissue
- drug induced
- protein kinase