A novel GSK-3 inhibitor binds to GSK-3β via a reversible, time and Cys-199-dependent mechanism was written by Ghazanfari, Davoud;Noori, Mahboubeh S.;Bergmeier, Stephen C.;Hines, Jennifer V.;McCall, Kelly D.;Goetz, Douglas J.. And the article was included in Bioorganic & Medicinal Chemistry in 2021.SDS of cas: 487021-52-3 This article mentions the following:
Glycogen synthase kinase-3 (GSK-3) has been implicated in numerous pathologies making GSK-3 an attractive therapeutic target. Our group has identified a compound termed COB-187 that is a potent and selective inhibitor of GSK-3. In this study, we probed the mechanism by which COB-187 inhibits GSK-3β. Progress curves, generated via real-time monitoring of kinase activity, indicated that COB-187 inhibition of GSK-3β is time-dependent and subsequent jump dilution assays revealed that COB-187 binding to GSK-3β is reversible. Further, a plot of the kinetic constant (kobs) vs. COB-187 concentration suggested that, within the range of concentrations studied, COB-187 binds to GSK-3β via an induced-fit mechanism. There is a critical cysteine residue at the entry to the active site of GSK-3β (Cys-199). We generated a mutant version of GSK-3β wherein Cys-199 was substituted with an alanine. This mutation caused a dramatic decrease in the activity of COB-187; specifically, an IC50 in the nM range for wild type vs. >100μM for the mutant. A screen of COB-187 against 34 kinases that contain a conserved cysteine in their active site revealed that COB-187 is highly selective for GSK-3 indicating that COB-187s inhibition of GSK-3β via Cys-199 is specific. Combined, these findings suggest that COB-187 inhibits GSK-3β via a specific, reversible, time and Cys-199-dependent mechanism. In the experiment, the researchers used many compounds, for example, 1-(4-Methoxybenzyl)-3-(5-nitrothiazol-2-yl)urea (cas: 487021-52-3SDS of cas: 487021-52-3).
1-(4-Methoxybenzyl)-3-(5-nitrothiazol-2-yl)urea (cas: 487021-52-3) belongs to thiazole derivatives. The higher aromaticity of thiazole is due to delocalization of a lone pair of sulfur electrons across the ring, which is evidenced by chemical shifts of ring hydrogen at δ 7.27 and 8.77 ppm (C2 and C4), indicating diamagnetic ring current. Thiazole is a versatile building block for the construction and lead generation of new drug discoveries. Numerous diazole-based compounds are in clinical use as anticancer, antileukemic, antiinflammatory, antiviral, antifungal, antirheumatic, immunomodulator, and antiparasitic agents.SDS of cas: 487021-52-3
Referemce:
Thiazole | C3H3NS – PubChem,
Thiazole | chemical compound | Britannica