新型布鲁顿氏酪氨酸激酶蛋白水解靶向嵌合体(BTK PROTAC)的设计合成及活性评价
Design,synthesis and biological evaluation of novel compounds of BTK PROTAC
许子威 1周卯 2高安慧 3桂双英 4白海云5
作者信息
- 1. 安徽中医药大学,合肥 230012;南通市海门长三角药物高等研究院,江苏 南通 226133
- 2. 沈阳药科大学,沈阳 110016;南通市海门长三角药物高等研究院,江苏 南通 226133
- 3. 南通市海门长三角药物高等研究院,江苏 南通 226133;百极弘烨医药科技有限公司,江苏 南通 226133
- 4. 安徽中医药大学,合肥 230012;药物制剂技术与应用安徽省重点实验室,合肥 230012
- 5. 百极弘烨医药科技有限公司,江苏 南通 226133
- 折叠
摘要
目的 设计合成新型布鲁顿氏酪氨酸激酶蛋白水解靶向嵌合体(BTK PROTAC),并在体外评估这些分子对BTK蛋白的降解活性.方法 以Nurix Therapeutics公司临床化合物NX-5948为先导化合物,分析其与靶蛋白的相互作用,通过引入并环代替吡嗪胺的骨架跃迁思路对其进行结构改造,成功合成了一系列新型BTK PROTACs,通过时间分辨荧光共振能量转移技术(TR-FRET)、MTS法和蛋白质免疫印迹法分别测定目标化合物的激酶活性、细胞增殖抑制活性和BTK蛋白降解活性.结果 共合成6个目标化合物(化合物B～G),活性测试结果显示,大部分化合物都具有优异的细胞增殖抑制活性和BTK降解活性,其中化合物B表现出较优的BTK蛋白降解能力,其半数最大降解浓度(DC50)值约为0.1 nmol·L-1.结论 基于NX-5948,通过骨架跃迁的方法设计合成了一类新颖的BTK PROTAC化合物,进行了构效关系的初步探索,可为BTK PROTAC降解剂的进一步研究提供参考.
Abstract
Objective To design and synthesize novel Bruton's tyrosine kinase protac(BTK PROTAC)molecules,and evaluate their degradation activity towards BTK protein in vitro.Methods With clinical compound NX-5968 from Nurix Therapeutics as a lead compound,its interaction with the target protein was analyzed.A series of novel BTK PROTACs were successfully synthesized by structural modification by introducing a skeleton transition of cyclic substitution for pyrazine amine.The kinase activity,cell proliferation inhibitory activity,and BTK degradation activity of the target compounds were measured by time-resolved fluorescence resonance energy transfer(TR-FRET),MTS and Western blot,respectively.Results Totally 6 target compounds were synthesized(compound B～G).The activity test showed that most compounds had excellent cell proliferation inhibition and BTK degradation.Compound B presented better BTK degradation ability,with a DC50 of about 0.1 nmol·L-1.Conclusion Based on NX-5948,a class of novel BTK PROTACs are designed and synthesized by skeleton transition,and their structure-activity relationship is preliminarily explored,providing reference for in-depth research on BTK PROTAC degraders.
关键词
布鲁顿氏酪氨酸激酶/蛋白水解靶向嵌合体/NX-5948/BTK/PROTAC/抗肿瘤活性Key words
Bruton's tyrosine kinase/protein hydrolysis-targeted chimera/NX-5948/BTK PROTAC/antitumor activity引用本文复制引用
出版年
2024
NETL
NSTL
万方数据