文献类型：期刊文献

英文题名：Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors

作者：Diao, Yanyan[1];Fang, Xiaoyu[1];Song, Peiran[2,3,4];Lai, Mengzhen[2,3,5];Tong, Linjiang[2,3];Hao, Yongjia[1];Dou, Dou[1];Liu, Yingqiang[2,3];Ding, Jian[2,3,4];Zhao, Zhenjiang[1];Xie, Hua[2,3];Li, Honglin[1]

机构：[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

年份：2019

卷号：27

期号：15

起止页码：3390

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000476649400020)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), the National Natural Science Foundation of China (grant 81825020), the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002), and the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：Bruton's tyrosine kinase; B-cell malignancies; Potent inhibitors; Structure-activity relationship; Cellular activities

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.