期刊
BIOCHEMISTRY
卷 58, 期 30, 页码 3225-3231出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.9b00499
关键词
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资金
- NCI [R01 CA090265]
- NIGMS [P41 GM094060]
- China Scholarship Council
- NIH T32 Training Grant [GM008804]
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.
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