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
常晏祥 1苏明波 2池岛乔 3白海云2
作者信息
- 1. 沈阳药科大学 无涯创新学院,辽宁 沈阳 110016;长三角药物高等研究院,江苏 南通 226133
- 2. 长三角药物高等研究院,江苏 南通 226133;百极弘烨(南通)医药科技有限公司,江苏 南通 226126
- 3. 沈阳药科大学 无涯创新学院,辽宁 沈阳 110016
- 折叠
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(IC50=7.15 nmol·L-1)和BTK降解活性(DC50<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.
Abstract
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(IC50=7.15 nmol·L-1)and BTK degradation activity(DC50<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Key words
BTK/proteolysis-targeting chimeras/protein degradation/proliferative inhibitory activity引用本文复制引用
出版年
2024
NETL
NSTL
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