Novel Pyridine Bioisostere of Cabozantinib as a Potent c-Met Kinase Inhibitor: Synthesis and Anti-Tumor Activity against Hepatocellular Carcinoma.

ABSTRACT: Two novel bioisosteres of cabozantinib, 3 and 4, were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (3) and pyridine (4), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal-epithelial transition factor (c-Met) inhibitory activities at 1 μM concentration (4% inhibition of 3 vs. 94% inhibition of 4). The IC₅₀ value of compound 4 was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that 4 includes the preferred conformation for the binding to c-Met in the conformational ensemble, but 3 does not. The anti-proliferative activity of compound 4 against he

SUBMITTER: Karmacharya U 

PROVIDER: S-EPMC8468607 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature