Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Bioorg Med Chem. 2020 May 15;28(10):115453. doi: 10.1016/j.bmc.2020.115453. Epub 2020 Mar 28.
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.
成纤维细胞生长因子受体 3（FGFR3）是治疗膀胱癌的一个有吸引力的治疗靶点。我们使用基于结构的药物设计（SBDD）方法，鉴定了 1,3,5-三嗪衍生物 18b 和嘧啶衍生物 40a，它们对血管内皮生长因子受体 2（VEGFR2）具有强大且高度选择性的 FGFR3 抑制活性。X 射线晶体结构分析表明，18b 与位于溶剂区域（Lys476 和 Met488）的氨基酸残基之间以及 40a 与 FGFR3 的后袋中位于 Met529 的氨基酸残基之间的相互作用可能是其具有强大的 FGFR3 抑制活性和对 VEGFR2 的高激酶选择性的基础。
