文献类型：期刊文献

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

作者：Chen, Haiyang[1];Song, Peiran[2,3,4];Diao, Yanyan[1];Hao, Yongjia[1];Dou, Dou[1];Wang, Wanqi[1];Fang, Xiaoyu[1];Wang, Yanling[1];Zhao, Zhenjiang[1];Ding, Jian[2];Li, Honglin[1];Xie, Hua[2];Xu, Yufang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;[3]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[4]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

年份：2018

卷号：9

期号：4

起止页码：697

外文期刊名：MEDCHEMCOMM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000435859400010)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501 and the Fundamental Research Funds for the Central Universities.

语种：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.