Substrate Competitive GSK-3 Inhibitors {single bond} strategy and Implications

Hagit Eldar-Finkelman*, Avital Licht-Murava, Shmuel Pietrokovski, Miriam Eisenstein

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations


Glycogen synthase kinase-3 (GSK-3) is a highly conserved protein serine/threonine kinase ubiquitously distributed in eukaryotes as a constitutively active enzyme. Abnormally high GSK-3 activity has been implicated in several pathological disorders, including diabetes and neuron degenerative and affective disorders. This led to the hypothesis that inhibition of GSK-3 may have therapeutic benefit. Most GSK-3 inhibitors developed so far compete with ATP and often show limited specificity. Our goal is to develop inhibitors that compete with GSK-3 substrates, as this type of inhibitor is more specific and may be useful for clinical applications. We have employed computational, biochemical, and molecular analyses to gain in-depth understanding of GSK-3's substrate recognition. Here we argue that GSK-3 is a promising drug discovery target and describe the strategy and practice for developing specific substrate-competitive inhibitors of GSK-3.

Original languageEnglish
Pages (from-to)598-603
Number of pages6
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Issue number3
StatePublished - Mar 2010


  • GSK-3
  • Inhibitors
  • Phosphorylation
  • Protein kinase
  • Substrate recognition


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