Department of Stomatology, Shenzhen Second People's Hospital, Shenzhen, China.
School of Biomedical Engineering, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Shenzhen University Medical School, Shenzhen, China.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2247183. doi: 10.1080/14756366.2023.2247183.
As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, exhibited potency against several c-Met mutants. Mechanistically, not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that could be an antitumor candidate meriting further development.
作为我们不断努力发现新型 c-Met 抑制剂作为抗肿瘤药物的一部分，设计、合成了四个系列的噻唑/噻二唑甲酰胺衍生类似物，并对其活性进行了评价，以评估其对 c-Met 和四种人癌细胞系的抑制作用。经过五轮结构-活性关系优化，发现化合物在生化和细胞测定中均是最有前途的抑制剂。此外，化合物对几种 c-Met 突变体具有抑制活性。在机制上，化合物不仅诱导 MKN-45 细胞周期停滞和凋亡，而且在细胞和无细胞体系中抑制 c-Met 磷酸化。它在 BALB/c 小鼠中也表现出良好的药代动力学特征。此外，化合物与 c-Met 和 VEGFR-2 的结合模式为发现选择性 c-Met 抑制剂提供了新的见解。综上所述，这些结果表明化合物可能是一种有前途的抗肿瘤候选药物，值得进一步开发。
