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
