中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study

文献类型：期刊论文

作者Sun, Yin3,4; Tang, Haotian2,3; Wang, Xiaoyan3,4; Feng, Fang3; Fan, Tiantian2,3; Zhao, Dongmei4; Xiong, Bing2,3; Xie, Hua1,2,3; Liu, Tongchao3
刊名JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
出版日期2022-12-31
卷号37期号:1页码:1411-1425
关键词TBK1 inhibitors 1H-pyrazolo[3 4-b]pyridine structure-activity relationships (SARs) immune response cancer therapy
ISSN号1475-6366
DOI10.1080/14756366.2022.2076674
通讯作者Zhao, Dongmei(medchemzhao@163.com) ; Xiong, Bing(bxiong@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Liu, Tongchao(tongchao_liu@simm.ac.cn)
英文摘要sABSTRACT TANK-binding kinase 1 (TBK1), a noncanonical member of the inhibitor-kappaB kinases (IKKs) family, plays a vital role in coordinating the signalling pathways of innate immunity, involving in the process of neuroinflammation, autophagy, and oncogenesis. In current study, based on rational drug design strategy, we discovered a series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure-activity relationships (SARs). Through the several rounds of optimisation, compound 15y stood out as a potent inhibitor on TBK1 with an IC50 value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound 15y effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound 15y exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor 15y as lead compound for immune- and cancer-related drug discovery.
WOS关键词THERAPEUTIC TARGET ; KINASE ; ACTIVATION ; EXPRESSION ; MECHANISM ; DISCOVERY ; CANCERS ; ROLES ; IKK
资助项目Lingang Laboratory Grant[LG202103-02-01] ; Lingang Laboratory Grant[LG202103-02-02] ; National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[81773572]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000798219900001
出版者TAYLOR & FRANCIS LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301074]  
专题中国科学院上海药物研究所
通讯作者Zhao, Dongmei; Xiong, Bing; Xie, Hua; Liu, Tongchao
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Yin,Tang, Haotian,Wang, Xiaoyan,et al. Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study[J]. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,2022,37(1):1411-1425.
APA Sun, Yin.,Tang, Haotian.,Wang, Xiaoyan.,Feng, Fang.,Fan, Tiantian.,...&Liu, Tongchao.(2022).Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study.JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,37(1),1411-1425.
MLA Sun, Yin,et al."Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study".JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 37.1(2022):1411-1425.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。