%0 Journal Article %T 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 %A Lai Meng-zhen %A Song Pei-ran %A Dou Dou %A Diao Yan-yan %A Tong Lin-jiang %A Zhang Tao %A Xie Hua %A Li Hong-lin %A Ding Jian %J Acta Pharmacologica Sinica %D 2020 %B 2020 %9 %! 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 %K %X >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 IC 50 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. %U http://www.chinaphar.com/article/view/10111 %V 41 %N 3 %P 415-422 %@ 1745-7254