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

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5669-5673. doi: 10.1016/j.bmcl.2016.10.060. Epub 2016 Oct 22.

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.

Keywords: 7-Azaindole; Fragment-linking strategy; Glycogen synthase kinase-3 beta; Inhibitor; Kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Models, Molecular
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology

Substances

  • 7-azaindole dimer
  • Enzyme Inhibitors
  • Indoles
  • Small Molecule Libraries
  • Glycogen Synthase Kinase 3 beta