有机化学 ›› 2020, Vol. 40 ›› Issue (1): 84-94.DOI: 10.6023/cjoc201904073 上一篇    下一篇

研究论文

通过FGF401的构效关系研究发现一种新颖的FGFR4选择性抑制剂

孙长安, 房雷, 苟少华   

  1. 东南大学化学化工学院 江苏省生物药物高技术研究重点实验室 南京 211189
  • 收稿日期:2019-04-29 修回日期:2019-08-31 出版日期:2020-01-25 发布日期:2019-09-18
  • 通讯作者: 苟少华, 房雷 E-mail:sgou@seu.edu.cn;lei.fang@seu.edu.cn
  • 基金资助:
    江苏省高等学校优势学科发展基金(No.1107047002)和国家科技重大专项基金(No.2013ZX09402102-001-006)资助项目.

Discovery of a Novel FGFR4 Selective Inhibitor via Structure-Activity Relationship Studies of FGF401

Sun Chang'an, Fang Lei, Gou Shaohua   

  1. Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189
  • Received:2019-04-29 Revised:2019-08-31 Online:2020-01-25 Published:2019-09-18
  • Supported by:
    Project supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. 1107047002) and the National Science and Technology Major Foundation of China (No. 2013ZX09402102-001-006).

设计并合成了一系列FGF401类似物以研究其FGFR4抑制、抗肿瘤活性及其构效关系.研究发现了N-(5-氰基-4-((2-甲氧基乙基氨基)吡啶-2-基)-7-甲酰基-6-((N-甲基四氢吡喃-4-甲酰胺)甲基-1,2,3,4-四氢-1,8-萘啶-1-甲酰胺(8ac)不仅在酶和细胞学水平上对FGFR4具有强效的的抑制活性,并表现出了出色的选择性.其活性及选择性优于阳性对照FGF401,并且在HCC(hepatocellular carcinoma)动物移植瘤模型中显著抑制肿瘤生长,还引起了肿瘤萎缩.

关键词: 选择性FGFR4抑制剂, FGF401类似物, 构效关系, 肝细胞癌

A set of analogues of FRF401 were designed and synthesized, and their FGFR4 inhibition and antitumor activity as well as the structure-activity relationship (SAR) studies were screened. It was found that N-(5-cyano-4-((2-methoxyethyl)-amino)pyridin-2-yl)-7-formyl-6-((N-methyltetrahydro-2H-pyran-4-carboxamido)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-carboxamide (8ac) not only showed superior FGFR4 inhibitory activity compared with FGF401 and excellent selectivity in enzymatic and cellular level, but also dramatically inhibited tumor growth and induced tumor regression in hepatocellular carcinoma xenograft model.

Key words: selective FGFR4 inhibitor, analogues of FRF401, structure-activity relationship, hepatocellular carcinoma