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

Abstract：

: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 19nM. 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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Kim J,Moon Y,Hong S

doi

10.1016/j.bmcl.2016.10.060

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

5669-5673

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)31098-8

journal_volume

26

pub_type

杂志文章

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