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Biochemical pharmacology

Biochemical pharmacology

IF: 5.3
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A novel covalent inhibitor alleviates type 2 diabetes mellitus by restraining GSK-3β

Published:4 August 2025 DOI: 10.1016/j.bcp.2025.117205
Shanhui Zhang , Fuhui Zhao , Changluan Pan , Yajing Wang , Zhangxiang Yang , Jing Yang , Yunniao Meng , Shaofang Lv , Jiayu Huang , Li Dong , Lei Li , Yongxi Dong

Abstract

Type 2 diabetes (T2DM), which is characterized by insulin resistance and diminished sensitivity, accounts for more than 90?% of the incidence rate of diabetes. At present, the drugs used to treat T2DM in clinic are restricted due to their poor compliance or serious adverse reactions. The abnormally elevated activity of GSK-3β plays an important regulatory role in the occurrence and development of T2DM. Herein, we report the therapeutic effect of a GSK-3β covalent inhibitor N-(3-(4-benzyl-3,5-dioxo-1,2,4-thiadiazol-2-yl) phenyl) acrylamide (GL10a), which was discovered by our group with excellent inhibitory activity and homologous kinase selectivity. Further research had confirmed that GL10a could inhibit the activity of GSK-3β, thereby increasing the hepatic glycogen synthesis, restoring glucose homeostasis, regulating insulin signaling pathways, and improving pancreatic β-cell function with consequent increase in insulin secretion. Additionally, our findings revealed that GL10a exerted beneficial effects on gut microbiota dysbiosis in T2DM, which may contribute to its therapeutic efficacy and facilitate disease recovery. These comprehensive pharmacological properties positioned GL10a as a promising candidate, potentially offering novel therapeutic strategies and clinical options for T2DM management.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
2H-Indol-2-one, 1,3-dihydro-3-(2-pyridinylmethylene)-, (3Z)- 187325-53-7 C14H10N2O 43 suppliers Inquiry
2H-Indol-2-one, 1,3-dihydro-3-(2-pyridinylmethylene)-, (3Z)- 187325-53-7 C14H10N2O 43 suppliers Inquiry
2H-Indol-2-one, 1,3-dihydro-3-(2-pyridinylmethylene)-, (3Z)- 187325-53-7 C14H10N2O 43 suppliers Inquiry
2H-Indol-2-one, 1,3-dihydro-3-(2-pyridinylmethylene)-, (3Z)- 187325-53-7 C14H10N2O 43 suppliers Inquiry

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