Evaluation of Anti-Proliferative Activity of Imidazole Derivatives in BCR/ABL1 Positive Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a myelo-proliferative disease characterized by a reciprocal translocation between chromosome 9 and chromosome 22 leading to increased proliferation of granulocytic cell lineage leads to high number of granulocytes and their immature precursors in blood profile. Present therapeutic strategies like chemotherapies along with targeted therapies for leukemia proved insufficient as disease remission and adaptive resistance along with cancer stem cells are chief factors behind plasticity as a treatment response in leukemia. Intrinsic and acquired mutations in BCR/ABL1 positive CML are salient reason of resistance development to tyrosine kinase inhibitors, the frontline therapeutic option. Range of imidazole derivatives have already exhibited anticancer potential in various cancers. The current research investigated four novel imidazole derivatives L7, L4, R-35, and R-NIM04 for their anti-leukemic potential and possible mechanism of action in BCR/ABL1 positive CML cells through In-silico and In-vitro approaches. Molecular docking was performed to shortlist the possible target candidates for these compounds followed by in-vitro cytotoxicity investigation using MTT assay. Only L7 was able to interfere with proliferation of CML cells in-vitro. Our In-silico findings shows, Breakpoint Cluster Region protein (BCR) as a potential drug target for L7 (B.E -7.25 kcal/mol). Subsequently, treatment with L7 at different concentrations interferes with the proliferation potential of BCR/ABL1 positive CML cells with p-values<0.05. Following MTT assay, RT-PCR findings indicated the downregulation of AXL-RTK and c-Myc suggesting that L7 interferes with Wnt/ꞵ-Catenin signaling pathway and reduces cellular proliferation by targeting fusion gene BCR/ABL1 in CML cells. Hence this research proffers L7 imidazole derivative as a potential therapeutic option for BCR/ABL1 positive CML