Identification of Potential GSK3α Ligands and Prediction of their Drug-like Properties

Glycogen synthase kinase 3 (GSK3) is a pivotal serine/threonine kinase regulating key process such as glycogen synthase, apoptosis and cell-cycle progression. The enzyme is a significant participant of PI3K/PTEN/AKT/GSK3/mTORC1 pathway and implicated in various human cancers. Of the two isoforms α and β in mammals GSK3β is extensively studied in cancer than GSK3α. The present study demonstrated expression of GSK3Α mRNA to be remarkably associated with poor RFS (Relapse Free Survival) in breast cancer patients using KM plotter (Kaplan-Meier plotter). TMN plot revealed a significant (p<0.0001) difference in GSK3A gene expression among the tumour and normal tissue as determined by Wilcoxon Signed Rank Test using both gene chip and RNA sequence data. ROC analysis also revealed the predictive significance of GSK3Α in patients administered endocrine therapy, anti-HER2 therapy and chemotherapy. Considering the importance of this enzyme, potential GSK3α ligands were also identified by molecular docking and ADMET analysis. Four compounds viz.(+/)-Synephrine, LTURM34, 2-Dehydro-3-deoxy-L-fuconate, 603288-22-8 (LY2090314) were found to target GSK3α with favourable pharmacological properties and were found to be non-toxic. These compounds can further be explored for their potential anticancer activity with GSK3α as the primary target.