Document Type: Research Articles
Department of Molecular Oncology, Cancer Institute (WIA), Adyar, Chennai, India.
Background: Targeted therapy in the form of highly selective tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). However, mutations in the kinase domain contribute to drug resistance against TKIs which compromises the treatment response. Our aim is to explore regions outside the BCR-ABL oncoprotein to identify potential therapeutic targets to curb drug resistance by targeting growth factor receptor-bound protein-2 (Grb-2) which binds to BCR-ABL at the phosphorylated tyrosine (Y177) thereby activating the Ras and PI3K/AKT signaling pathway. Methods: We have used in silico methods to repurpose drugs for identifying their potential to inhibit the binding of Grb-2 with Y177 by occupying the active binding site of the BCR domain. Results: Differentially expressed genes from GEO dataset were found to be associated with hematopoietic cell lineage, NK cell-mediated cytotoxicity, NF-κB and chemokine signaling, cytokine-cytokine receptor interaction, histidine metabolism and transcriptional misregulation in cancer. The fold recognition method of SPARKS-X tool was used to model the BCR domain (Z-score = 8.21). Connectivity Map generated a drug list based on the gene expression profile, which were docked with BCR. Schrodinger XP glide docking identified Diphosphopyridine nucleotide, Hesperidin, Butirosin, Ovoflavin, and Nor-dihydroguaiaretic acid to show strong interaction in close proximity to the active binding pocket containing Y177 of the target protein and was further validated using iGEMDOCK and Parallelized Open Babel and AutoDock suite Pipeline (POAP). Conclusion: Our study not only extends our current knowledge about repurposing drugs for newer indications but also provides a route towards combinatorial therapy with standard drugs used for CML treatment. However, the efficacy of these repurposed drugs needs to be further investigated using in vitro and in vivo studies.