Wei Peng, Liu Bo, Wang Ruifeng, Gao Yinglei, Li Lanlan, Ma Yuchi, Qian Zhiwei, Chen Yuelei, Cheng Maosheng, Geng Meiyu, Shen Jingkang, Zhao Dongmei, Ai Jing, Xiong Bing
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharm Sin B. 2019 Mar;9(2):351-368. doi: 10.1016/j.apsb.2018.12.008. Epub 2018 Dec 26.
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure-activity relationship was elaborated. Together with metabolic stability tests and pharmacokinetic profiling, a representative compound () was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.
基因组改变常见于成纤维细胞生长因子受体（FGFRs）的信号通路中。尽管市场上尚无选择性FGFR抑制剂，但几种有前景的抑制剂已在临床试验中进行了研究，并在患者中显示出令人鼓舞的疗效。通过设计FGFR选择性增强基序二甲氧基苯基团与我们先前鉴定的新型骨架之间的杂合物，我们发现了一系列新的强效FGFR抑制剂，其中最佳的一种显示出亚纳摩尔的酶活性。经过几轮优化并结合解析的晶体结构，阐述了详细的构效关系。连同代谢稳定性测试和药代动力学分析，选择了一种代表性化合物（）并在异种移植小鼠模型中进行测试，结果表明该抑制剂对具有FGFR基因改变的肿瘤有效，具有进一步开发的潜力。
