GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Int J Mol Sci. 2023 Apr 19;24(8):7541. doi: 10.3390/ijms24087541.


Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.

Keywords: Alzheimer’s disease; Pocketron; cancer; drug discovery; inhibitors.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate* / metabolism
  • Binding Sites
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Protein Kinase Inhibitors* / chemistry


  • Glycogen Synthase Kinase 3 beta
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate

Grants and funding

This research received no external funding.