Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors
Diao, Yanyan1; Fang, Xiaoyu1; Song, Peiran2,3,4; Lai, Mengzhen2,3,5; Tong, Linjiang2,3; Hao, Yongjia1; Dou, Dou1; Liu, Yingqiang2,3; Ding, Jian2,3,4; Zhao, Zhenjiang1
2019-08
发表期刊BIOORGANIC & MEDICINAL CHEMISTRY
ISSN0968-0896
卷号27期号:15页码:3390-3395
发表状态已发表
DOI10.1016/j.bmc.2019.06.023
摘要Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[ 4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC50 = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 mu M.
关键词Bruton's tyrosine kinase B-cell malignancies Potent inhibitors Structure-activity relationship Cellular activities
收录类别SCI ; SCIE
语种英语
资助项目National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2018ZX09711002]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
WOS类目Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
WOS记录号WOS:000476649400020
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS关键词BTK INHIBITORS ; ACTIVATION ; TARGET ; TEC
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/61055
专题生命科学与技术学院_博士生
生命科学与技术学院_特聘教授组_丁健组
通讯作者Zhao, Zhenjiang; Xie, Hua; Li, Honglin
作者单位1.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China
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GB/T 7714
Diao, Yanyan,Fang, Xiaoyu,Song, Peiran,et al. Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(15):3390-3395.
APA Diao, Yanyan.,Fang, Xiaoyu.,Song, Peiran.,Lai, Mengzhen.,Tong, Linjiang.,...&Li, Honglin.(2019).Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,27(15),3390-3395.
MLA Diao, Yanyan,et al."Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 27.15(2019):3390-3395.
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