Synthesis and biological evaluation of novel aromatic amide derivatives as potential BCR-ABL inhibitors

Abstract

BCR-ABL1 kinase is a key driver of the pathophysiology of chronic myeloid leukemia (CML). Current treatments need to broaden the chemical diversity of BCR-ABL1 kinase inhibitors to overcome drug resistance. We designed and synthesized a series of aromatic amide derivatives based on several generations of BCR-ABL1 kinase inhibitors. Biological studies showed that compared with Imatinib, these compounds showed significant proliferation inhibitory activities of HL-60 and K562 in cell activity assay. Compounds 4g and 4j exhibited significant anti-tumor activity against the K562 cells with IC₅₀ values of 6.03 ± 0.49 μM and 5.66 ± 2.06 μM respectively. Compounds 4g and 4j, as potential BCR-ABL1 inhibitors, inhibit the phosphorylation of ABL1 and CRKL in a dose-dependent manner. Therefore, compounds 4g and 4j can be used as a starting point for further optimization.

Keywords: Anti-tumor activity; Apoptosis; Aromatic amide derivatives; BCR-ABL1 kinase inhibitor; Cell-cycle; Chronic myeloid leukemia.