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, <b>3</b> and <b>4</b>, were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (<b>3</b>) and pyridine (<b>4</b>), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal-epithelial transition factor (<i>c</i>-Met) inhibitory activities at 1 μM concentration (4% inhibition of <b>3</b> vs. 94% inhibition of <b>4</b>). The IC₅₀ value of compound <b>4</b> was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that <b>4</b> includes the preferred conformation for the binding to <i>c</i>-Met in the conformational ensemble, but <b>3</b> does not. The anti-proliferative activity of compound <b>4</b> against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas <b>3</b> did not show a significant anti-proliferative activity. Moreover, the tumor selectivity of compound <b>4</b> toward hepatocellular carcinoma cell lines was higher than that of cabozantinib. In the xenograft <i>chick</i> tumor model, compound <b>4</b> inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound <b>4</b> may be a good therapeutic candidate against hepatocellular carcinoma.