College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.
Int J Mol Sci. 2021 Sep 7;22(18):9685. doi: 10.3390/ijms22189685.
Two novel bioisosteres of cabozantinib, and , were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine () and pyridine (), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal-epithelial transition factor (-Met) inhibitory activities at 1 μM concentration (4% inhibition of vs. 94% inhibition of ). The IC value of compound was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that includes the preferred conformation for the binding to -Met in the conformational ensemble, but does not. The anti-proliferative activity of compound against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas did not show a significant anti-proliferative activity. Moreover, the tumor selectivity of compound toward hepatocellular carcinoma cell lines was higher than that of cabozantinib. In the xenograft tumor model, compound inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound may be a good therapeutic candidate against hepatocellular carcinoma.
设计并合成了卡博替尼的两个新型生物等排体 和 。卡博替尼结构中心的苯环分别被三甲基吡啶（）和吡啶（）取代。令人惊讶的是，这两种化合物在 1 μM 浓度下对间充质上皮转化因子（-Met）表现出截然不同的抑制活性（化合物对 的抑制率为 4%，而对 的抑制率为 94%）。化合物 的 IC 值为 4.9 nM，与卡博替尼（5.4 nM）相似。基于配体的对接研究表明， 包含与 -Met 结合的首选构象，但 不包含。化合物 对肝癌（Hep3B 和 Huh7）和非小细胞肺癌（A549 和 H1299）细胞系的增殖抑制活性优于卡博替尼，而 则没有表现出明显的增殖抑制活性。此外，化合物 对肝癌细胞系的肿瘤选择性高于卡博替尼。在异种移植 Hep3B 肿瘤模型中，化合物 对 Hep3B 肿瘤生长的抑制作用明显强于卡博替尼。本研究表明，化合物 可能是一种治疗肝癌的良好候选药物。
