一种源于重氮醇氮原子增强的同工酶选择性 PTP1B 抑制剂。
An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.
机构信息
Department of Pharmacology and Toxicology, College of Pharmacy , University of Arizona , 1703 East Mabel Street , P.O. Box 210207, Tucson , Arizona 85721 , United States.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering , East China Normal University , Shanghai , China , 200062.
出版信息
Biochemistry. 2019 Jul 30;58(30):3225-3231. doi: 10.1021/acs.biochem.9b00499. Epub 2019 Jul 18.
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 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol () 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 to be an allosteric inhibitor of PTP1B with a submicromolar . Cellular analyses using C2C12 myoblasts indicated that restored insulin signaling and increased glucose uptake.
从天然产物库及其衍生物中筛选出能够抑制蛋白酪氨酸磷酸酶 1B（PTP1B）的物质，PTP1B 是治疗肥胖症和 II 型糖尿病的有效药物靶点。在初步筛选中具有活性的物质中，最有前途的是一种含有新型吡咯并吡唑并异喹啉骨架的化合物，该骨架是通过用肼处理雷地昔布（radicicol）得到的。与其他高度同源的非受体 PTP 相比，这种氮原子修饰的雷地昔布衍生物被发现对 PTP1B 具有选择性。生化评估、分子对接和突变分析表明，化合物 是 PTP1B 的别构抑制剂，其半数抑制浓度（IC50）为亚微摩尔级。使用 C2C12 成肌细胞进行的细胞分析表明，化合物 能够恢复胰岛素信号转导并增加葡萄糖摄取。
Zotero 插件