通过FGF401的构效关系研究发现一种新颖的FGFR4选择性抑制剂  

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

作　　者：孙长安 房雷[1] 苟少华[1] Sun Chang'an;Fang Lei;Gou Shaohua(Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering,Southeast University,Nanjing 211189)

机构地区：[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

出　　处：《有机化学》2020年第1期84-94,共11页Chinese Journal of Organic Chemistry

基　　金：江苏省高等学校优势学科发展基金(No.1107047002);国家科技重大专项基金(No.2013ZX09402102-001-006)资助项目。

摘　　要：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.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-2 H-pyran-4-carboxamido)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-carboxamide(8 ac) 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.

关 键 词：选择性FGFR4抑制剂 FGF401类似物 构效关系 肝细胞癌 

分 类 号：TQ460.1[化学工程—制药化工]