Inhibition of protein kinases by anticancer DNA intercalator, 4-butylaminopyrimido[4',5':4,5]thieno(2,3- b)quinoline

Targeting protein kinases (PKs) has been a promising strategy in treating Cancer, as PKs are key regulators of cell survival and proliferation. Here in this study, we studied the ability of pyrimido[4',5':4,5]thieno(2,3-b)quinolines (PTQ) to inhibit different PKs by performing computational docking and in vitro screening. Docking studies revealed that 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline (BPTQ) has a higher order of interaction with the kinase receptors than other PTQ derivatives. In vitro screening confirms that BPTQ inhibits VEGFR1/Flt-1 and Chk2, with the IC₅₀ values of 0.54 and 1.70 µmol/L, respectively. Further, cytotoxicity of BPTQ was measured by trypan blue assay. Treatment with BPTQ decreased the proliferation of HL-60 cells with an IC₅₀ value of 12 µmol/L and induces Apoptosis, as explicated by the fall in the mitochondrial membrane potential, annexin V labeling and increased expression of Caspase-3. Taken together, these data suggest that BPTQ possess ability to inhibit PKs and to induce cell death in human promyelocytic leukemia cells.

Anticancer drugs; Apoptosis; Chemotherapy; DNA intercalator; Kinase inhibitor; Molecular docking.