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(DC50)小于1 nM;并且所有目标化合物24h最大降解程度(Dmax)均略优于NX-5948,为进一步化合物改造提供结构依据.
Design,Synthesis and Biological Activity Evaluation of Novel BTK-PROTAC Molecules
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 syn-thesized.To study the effects of different linkers and E3 ligand on protein degradation activity,com-pounds 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(DC50)were less than 1 nM.Moreover,the maximum degradation degree(Dmax)of all target compounds at 24 h was better than that of NX-5948,which provided a structural basis for further compound modification.
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