新型BTK PROTAC降解剂的设计合成及活性评价  

Design,synthesis and biological activity evaluation of novel BTK PROTAC degrader

作　　者：常晏祥 苏明波 池岛乔[1] 白海云 CHANG Yanxiang;SU Mingbo;IKEJIMA Takashi;BAI Haiyun(Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China;Yangtze River Delta Drug Advanced Research Institute,Nantong 226133,China;Bipolar Hongye(Nantong)Pharmaceutical Co.,Ltd.,Nantong 226126,China)

机构地区：[1]沈阳药科大学无涯创新学院,辽宁沈阳110016 [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226126

出　　处：《沈阳药科大学学报》2024年第8期1055-1066,共12页Journal of Shenyang Pharmaceutical University

摘　　要：目的设计合成系列以伊布替尼类似物为布鲁顿酪氨酸激酶(bruton′s tyrosine kinase,BTK)激酶配体的蛋白降解靶向嵌合体(proteolysis targeting chimeras,PROTAC)降解剂,并初步评价其体外活性。方法以3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺为起始原料,通过取代、还原胺化、脱保护和水解等反应合成一系列新型PROTAC;通过MTS法和蛋白免疫印迹法(Western-blot)分别测定目标化合物对OCI-LY10细胞的增殖抑制能力和BTK降解活性;通过分子对接考察分子配体与BTK蛋白的结合模式。结果共合成了14个BTK PROTAC降解剂,大部分化合物都具有一定的体外活性,其中化合物15a表现出了较好的细胞增殖抑制活性(IC_(50)=7.15 nmol·L^(-1))和BTK降解活性(DC_(50)<10 nmol·L^(-1))。结论合成了结构新颖、活性较好的BTK PROTAC降解剂,对其构效关系进行了初步探索,可为BTK PROTAC降解剂的进一步研究提供参考。Objective To design and synthesize BTK PROTACs with ibrutinib analogues as ligands of BTK and thalidomide analogues as ligands of E3 ligase,and evaluate its in vitro activity.Methods As a starting material,3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine was used to modify and synthesize new BTK PROTACs by substitution,reduction amination,deprotection,hydrolysis and other reactions;the OCI-LY10 proliferative inhibitory activity and BTK degradation activity of the target.compounds were determined by MTS and Western-blot;the binding mode of molecular ligands to BTK was determined by molecular docking.Results A total of 14 PROTACs were synthesized,and most of the.compounds exhibited certain amount of in vitro activity,among which.compound 15a showed excellent cell proliferative inhibitory activity(IC_(50)= 7.15 nmol·L~(-1)) and BTK degradation activity(DC_(50)<10 nmol·L~(-1)).Conclusions BTK PROTACs with novel structure and excellent activity were synthesized,and the structure-activity relationship was preliminarily explored,which could provide a reference for further research on BTK PROTAC degrader.

关 键 词：布鲁顿酪氨酸激酶 蛋白质降解靶向嵌合体 蛋白降解 抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学]