Identification of lead small molecule inhibitors of glycogen synthase kinase-3 beta using a fragment-linking strategy

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• 作者：Jinhee Kim^a ; Yonghoon Moon^a ; ^b ; Sungwoo Hong^a ; ^b ; ^{hongorg@kaist.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Glycogen synthase kinase-3 beta ; Inhibitor ; Fragment-linking strategy ; 7-Azaindole ; Kinase
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5669-5673
• 全文大小：2091 K

文摘

Glycogen synthase kinase-3 beta (GSK3β) kinase serves as a promising therapeutic target for the treatment of various human diseases, such as diabetes, obesity, and Alzheimer’s disease. In this study, we report lead GSK3β inhibitors identified using a fragment-linking strategy. Through the systematic exploration, a six-atom chain unit bearing the rigid double bond was found to be a suitable linker connecting two fragments, which enables favorable contacts with backbone groups of residues in the pockets. As a consequence, potent GSK3β inhibitor 9i was found with IC₅₀ values of 19 nM. The binding mode analysis indicates that the activities of the inhibitors appear to be achieved by the establishment of multiple hydrogen bonds and hydrophobic interactions in the ATP-binding site of GSK3β. The good biochemical potencies and structural uniqueness of the inhibitors support consideration in the further study to optimize the biological activity.