Repurposing FDA-approved compounds to target JAK2 for colon cancer treatment

Abstract

Abstract Colorectal cancer is one of the common cancers worldwide and the second leading cause of cancer-related death. The current treatment has the inherent drawbacks and there is a need of developing a new treatment. Interleukin-6 a pleiotropic cytokine involved in immune regulation and activation of JAK2/STAT3 pathway in colorectal cancer. JAK2/STAT3 signaling pathway functions as a critical regulator of cell growth, differentiation, and immune expression. The abnormality in the JAK2/STAT3 pathway is involved in the tumorigenesis of colon cancer including apoptosis. In this study, we identified novel inhibitors for JAK2 protein by performing virtual screening against FDA-approved compounds. To address the selectivity issue, we implemented cross-docking method followed by DFT calculations to understand the chemical reactivity of the identified compounds. Additionally, molecular dynamics (MD) simulations were performed for the top FDA compounds against JAK2 to understand the molecular interactions and structural stability of the complex over a period of 200 ns. Our results indicated that ergotamine, entrectinib, exatecan, dihydroergotamine, and paritaprevir can be used as alternative drugs for colon cancer. In addition, ergotamine was found to efficiently lower the cell viability with IC50 values of 100 µM on colon cancer cell lines. The long-term inhibitory effect of the ergotamine led to a decrease in colony size, and the toxicity properties were studied using hemolysis assay. Our study shows the potential of targeting JAK2 as a novel approach to colon cancer treatment, and demonstrate that ergotamine as a promising effects as an anti-cancer drug. Graphical abstract

Keywords

• JAK2
• Colorectal cancer
• Drug repurposing
• Molecular docking
• Density functional theory
• Molecular dynamic simulation