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

Bioorg Med Chem Lett. 2023 Feb 1:81:129144. doi: 10.1016/j.bmcl.2023.129144.

Xiujun Wang ¹, Zhou Xu ¹, Jing Feng ¹, Gang Pan ¹, Xingbei He ¹, Mingxiao Lv ¹, Huijie Chen ¹, Wentao Jiang ², Jing Ji ³, Mingli Yang ⁴

Affiliations

1 College of Pharmacy, Jiangsu Ocean University, Lianyungang 222000, China.
2 College of Pharmacy, Jiangsu Ocean University, Lianyungang 222000, China; Department of Pharmacy, Kangda College of Nanjing Medical University, Lianyungang 222000, China.
3 College of Pharmacy, Jiangsu Ocean University, Lianyungang 222000, China. Electronic address: [email protected].
4 Department of Pharmacy, Kangda College of Nanjing Medical University, Lianyungang 222000, China. Electronic address: [email protected].

PMID: 36681201 DOI: 10.1016/j.bmcl.2023.129144

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.

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