Design, <i>In Silico</i> Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to Bcr-Abl Tyrosine Kinase

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is currently still an unmet need for effective and safe drugs to treat patients with resistance and intolerance to clinically used drugs. In this work, 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid were designed followed by in silico assessment of the inhibitory potential of these compounds against Bcr-Abl tyrosine kinase and determination of their antitumor activity on cell models of the K562 (chronic myeloid leukemia), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) lines. As a result of the joint analysis of computational and experimental data, three compounds exhibiting antitumor activity against cells of the K562 and HL-60 lines were identified. A lead compound demonstrating effective inhibition of the growth of these cells was found, as evidenced by the low values of IC50 equal to 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The results obtained indicate that the identified compounds form good scaffolds for the design of novel, effective and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.