Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors

doi:10.1039/c8md00019k

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors
	Chen, Haiyang 2; Song, Peiran 1,3,4; Diao, Yanyan 2; Hao, Yongjia 2; Dou, Dou 2; Wang, Wanqi 2; Fang, Xiaoyu 2; Wang, Yanling 2; Zhao, Zhenjiang 2; Ding, Jian1
刊名	MEDCHEMCOMM
	2018-04-01
卷号	9 期号:4 页码:697-704
ISSN号	2040-2503
DOI	10.1039/c8md00019k
文献子类	Article
英文摘要	Bruton's tyrosine kinase (BTK) plays a critical role in B cell receptor (BCR)-mediated signaling pathways responsible for the development and function of B cells, which makes it an attractive target for the treatment of many types of B-cell malignancies. Herein, a series of N5-substituted 6,7-dioxo-6,7-dihydropteridine-based, irreversible BTK inhibitors were reported with IC50 values ranging from 1.9 to 236.6 nM in the enzymatic inhibition assay. Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme, as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLC gamma 2. Overall, this series of compounds could provide a promising starting point for further development of potent BTK inhibitors for B-cell malignancy treatment.
资助项目	National Key Research and Development Program[2016YFA0502304] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[U1501501] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	CHRONIC LYMPHOCYTIC-LEUKEMIA ; B-CELL MALIGNANCY ; TEC FAMILY ; BTK ; ACTIVATION ; RECEPTOR ; DOMAIN ; EXPRESSION ; IBRUTINIB ; DISEASE
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000435859400010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279815]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Li, Honglin; Xie, Hua; Xu, Yufang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 2.East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Haiyang,Song, Peiran,Diao, Yanyan,et al. Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors[J]. MEDCHEMCOMM,2018,9(4):697-704.
APA	Chen, Haiyang.,Song, Peiran.,Diao, Yanyan.,Hao, Yongjia.,Dou, Dou.,...&Xu, Yufang.(2018).Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors.MEDCHEMCOMM,9(4),697-704.
MLA	Chen, Haiyang,et al."Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors".MEDCHEMCOMM 9.4(2018):697-704.