新型BTK-PROTAC分子的设计、合成及生物活性评价  

Design,Synthesis and Biological Activity Evaluation of Novel BTK-PROTAC Molecules

作　　者：葛子豪 周卯 查永骏 白海云 钟利 GE Zihao;ZHOU Mao;ZHA Yongjun;BAI Haiyun;ZHONG Li(College of Pharmacy,Anhui University of Chinese Medicine,Hefei 230012,China;Yangtze Delta Drug Advanced Research Institute,Nantong 226133,China;Biopolar Hongye(Nantong)Pharmaceutical Co.,Ltd.,Nantong 226133,China)

机构地区：[1]安徽中医药大学药学院,安徽合肥230012 [2]长三角药物高等研究院,江苏南通226133 [3]百极弘烨(南通)医药科技有限公司,江苏南通226133

出　　处：《合成化学》2024年第6期534-541,共8页Chinese Journal of Synthetic Chemistry

摘　　要：蛋白降解靶向嵌合体(PROTAC)技术在新药研发领域越来越受到重视。基于NX-5948的靶蛋白配体(Warhead)结构,采用5-氟吲哚代替吡嗪胺的思路进行改造,成功合成化合物A。为研究不同连接子(Linker)和E3配体对蛋白降解活性的影响,成功设计合成了化合物B~F,化合物A~F结构均经^(1)H NMR和MS表征。通过蛋白质免疫印迹法(Western blot,WB)分别测定目标化合物布鲁顿酪氨酸激酶(BTK)的降解活性。结果表明:化合物A、C、D、E、F都有近似于NX-5948的蛋白降解活性,其半数降解浓度(DC_(50))小于1 nM;并且所有目标化合物24 h最大降解程度(D_(max))均略优于NX-5948,为进一步化合物改造提供结构依据。Proteolysis-targeting chimera(PROTAC)has attracted more and more attention in the field of new drug research and development.In this paper,based on the ligand structure of NX-5948,5-fluoroindole was used to replace pyrazinamine for modification,and compound A was successfully synthesized.To study the effects of different linkers and E3 ligand on protein degradation activity,compounds B~F were successfully designed and synthesized.The structures of compounds A~F were characterized by^(1)H NMR and MS.Bruton′s tyrosine kinase(BTK)degradation activity of the target compounds were determined by Western blot(WB).The results showed that compounds A,C,D,E,and F all had protein degradation activities similar to those of NX-5948,and their half degradation concentrations(DC_(50))were less than 1 nM.Moreover,the maximum degradation degree(D_(max))of all target compounds at 24 h was better than that of NX-5948,which provided a structural basis for further compound modification.

关 键 词：蛋白降解靶向嵌合体 布鲁顿酪氨酸激酶 蛋白降解 合成 分子设计 

分 类 号：R914.5[医药卫生—药物化学]