文献类型：期刊文献

英文题名：Discovery and biological evaluation of N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide as potent Bruton's tyrosine kinase inhibitors

作者：Lai, Meng-zhen[1,2];Song, Pei-ran[2,3,4];Dou, Dou[5];Diao, Yan-yan[5];Tong, Lin-jiang[2,4];Zhang, Tao[2,3,4];Xie, Hua[2,4];Li, Hong-lin[5];Ding, Jian[2,3,4]

机构：[1]Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, 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]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;[4]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[5]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2020

卷号：41

期号：3

起止页码：415

外文期刊名：ACTA PHARMACOLOGICA SINICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000514159600013)】；

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

外文关键词：B cell receptor; Bruton's tyrosine kinase; ibrutinib; small-molecule inhibitor; B cell malignancies

摘要：Bruton's tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders; thus, it is an attractive target for the treatment of B cell related diseases. Here, we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives. Combining this evaluation with structure-activity relationship (SAR) analysis, we found that compound 2 exhibited potent BTK kinase inhibitory activity, with an IC50 of 7 nM. This derivative markedly inhibited BTK activation in TMD8 B cell lymphoma cells and thus inhibited the in vitro growth of the cells. Further studies revealed that compound 2 dose dependently arrested TMD8 cells at G(1) phase, accompanied by decreased levels of Rb, phosphorylated Rb, and cyclin D1. Moreover, following treatment with compound 2, TMD8 cells underwent apoptosis associated with PARP and caspase 3 cleavage. Interestingly, the results of the kinase activity assay on a small panel of 35 kinases showed that the kinase selectivity of compound 2 was superior to that of the first-generation inhibitor ibrutinib, suggesting that compound 2 could be a second-generation inhibitor of BTK. In conclusion, we identified a potent and highly selective BTK inhibitor worthy of further development.