摘要
目的设计合成以PF-562271类似物为黏着斑激酶(focal adhesion kinase,FAK)的配体,来那度胺或泊马度胺类似物为E3连接酶配体的PROTAC(proteolytic targeting chimera),并对其降解FAK蛋白的活性进行评价。方法以对氟硝基苯为起始原料,经取代、还原、脱除保护基、环合、还原、酰化等反应得到目标化合物。采用Western blot技术测试PROTAC分子对A549细胞中FAK蛋白的降解活性。结果与结论合成了6个PROTAC分子,目标化合物结构经1H-NMR和HR-MS确证。Western blot测试表明6个目标化合物对A549细胞中的FAK蛋白均具有降解活性,其中化合物Ⅱa的蛋白降解活性较强,在10 nmol·L^(-1)浓度下FAK蛋白降解率为52%,具有进一步研究价值,该研究为后续开展以FAK为靶点的PROATC分子的研究奠定了基础。
PROTAC with PF⁃562271 analog as FAK ligand,and lenalidomide or pomadolamine analogs as E3 ligands were designed and synthesized,and its activity of degrading FAK protein was evaluated.Starting form p⁃fluoronitrobenzene as the starting material,target compounds were obtained through substitution,reduction,deprotection,cyclization,reduction and acylation reactions.The structure of the target compounds were confirmed by 1H⁃NMR and HR⁃MS.Western blot results showed that most of the compounds had strong degradation activity against FAK in A549 cells,and reduced FAK protein level in a concentration⁃dependent manner.Among them,PROTACⅡa presented strong FAK degradation activity(52%degradation at 10 nmol·L^(-1)).
作者
王瑞峰
赵相欣
孙印
秦桥花
赵冬梅
WANG Rui-feng;ZHAO Xiang-xin;SUN Yin;QIN Qiao-hua;ZHAO Dong-mei(Department of Pharmacy,Shanxi Medical University,Taiyuan 030001,China;Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
2023年第7期481-489,共9页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(82204222)。
关键词
黏着斑激酶
蛋白降解靶向嵌合体
蛋白降解
focal adhesion kinase
proteolytic targeting chimera
protein degradation
