Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase

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Elena V. Koroleva¹, Anastasiya L. Ermolinskaya¹, Zhanna V. Ignatovich¹, Yury V. Kornoushenko², Alesia V. Panibrat², Vladimir I. Potkin³, Alexander M. Andrianov^2,a*

¹Institute of Chemistry of New Materials, National Academy of Sciences of Belarus, Minsk, 220141, Republic of Belarus

²Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, 220141, Republic of Belarus

³Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus

^* To whom correspondence should be addressed.

Received: December 27, 2023; Revised: May 7, 2024; Accepted: May 11, 2024

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Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC₅₀ values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures 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.

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KEY WORDS: Bcr-Abl tyrosine kinase, Bcr-Abl inhibitors, computer-aided drug design, molecular docking, molecular dynamics, biomedical testing, antitumor activity

DOI: 10.1134/S0006297924060099

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