| Autor: |
Xinyi Zhang, Weiwei Zhao, Feilong Wang, Wei Zhao, Liang Hu, Zhendong Xie, Xueyan Zhu, Peng Zhang, Yong Chu |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Results in Chemistry, Vol 8, Iss , Pp 101553- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2211-7156 |
| DOI: |
10.1016/j.rechem.2024.101553 |
| Popis: |
Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory-mediated diseases in animal models. Allosteric inhibitors inherently have better therapeutical value due to their higher specificity than ATP-competitive ones. In this paper, we reported the discovery of a novel series of N, N-dibenzylcinnamamide (DBCA) compounds as allosteric GSK-3β inhibitors via a scaffold hopping strategy. The in vitro enzymatic evaluation showed most DBCA derivatives have inhibitory effects on GSK-3β in a micromolar scale. Among them, seven compounds D-27 ∼ 33 showed activities at lower micromolar levels. Kinetic analysis revealed this type of compound inhibited GSK-3β by an allosteric modulation. The in vitro cytokine release assay demonstrated that D-33 could reduce the release of proinflammatory cytokines IL-1β and IL-6 while keeping IL-12 and TNF-α intact, indicating it might be a potential safer candidate for certain inflammatory conditions, such as neuroinflammatory diseases. Finally, docking studies were performed to suggest binding modes that explain the impacts of candidates on the enzyme. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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