Deciphering the mechanism of Indirubin and its derivatives in the inhibition of Imatinib resistance using a “drug target prediction-gene microarray analysis-protein network construction” strategy

Abstract

Abstract Background The introduction of imatinib revolutionized the treatment of chronic myeloid leukaemia (CML), substantially extending patient survival. However, imatinib resistance is currently a clinical problem for CML. It is very importantto find a strategy to inhibit imatinib resistance. Methods (1) We Identified indirubin and its derivatives and predicted its putative targets; (2) We downloaded data of the gene chip GSE2810 from the Gene Expression Omnibus (GEO) database and performed GEO2R analysis to obtain differentially expressed genes (DEGs); and (3) we constructed a P-P network of putative targets and DEGs to explore the mechanisms of action and to verify the results of molecular docking. Result We Identified a total of 42 small-molecule compounds, of which 15 affected 11 putative targets, indicating the potential to inhibit imatinib resistance; the results of molecular docking verified these results. Six biomarkers of imatinib resistance were characterised by analysing DEGs. Conclusion The 15 small molecule compounds inhibited imatinib resistance through the cytokine-cytokine receptor signalling pathway, the JAK-stat pathway, and the NF-KB signalling pathway. Indirubin and its derivatives may be new drugsthat can combat imatinib resistance.

Keywords

• Indirubin
• Derivatives
• Imatinib resistance
• Drug target prediction
• Gene microarray analysis
• Protein network construction