discoveryandbiologicalevaluationofn372methoxy44methylpiperazin1ylphenylamino4methyl2oxo2hpyrimido45d13oxazin14hylphenylacrylamideaspotentbrutonstyrosinekinaseinhibitors

doi:10.1038/s41401-019-0250-8

	discoveryandbiologicalevaluationofn372methoxy44methylpiperazin1ylphenylamino4methyl2oxo2hpyrimido45d13oxazin14hylphenylacrylamideaspotentbrutonstyrosinekinaseinhibitors
	Lai Mengzhen 1; Song Peiran 2; Dou Dou 3; Diao Yanyan 3; Tong Linjiang 2; Zhang Tao 2; Xie Hua 2; Li Honglin 3; Ding Jian 2
刊名	actapharmacologicasinica
	2020
卷号	41 期号:3 页码:415
关键词	B cell receptor Bruton’s tyrosine kinase ibrutinib small-molecule inhibitor B cell malignancies
ISSN号	1671-4083
DOI	10.1038/s41401-019-0250-8
英文摘要	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 pyrimido4,5-d1,3oxazin-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 G1 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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280775]
专题	中国科学院上海药物研究所
作者单位	1.南昌大学 2.中国科学院上海药物研究所 3.华东理工大学
推荐引用方式 GB/T 7714	Lai Mengzhen,Song Peiran,Dou Dou,et al. discoveryandbiologicalevaluationofn372methoxy44methylpiperazin1ylphenylamino4methyl2oxo2hpyrimido45d13oxazin14hylphenylacrylamideaspotentbrutonstyrosinekinaseinhibitors[J]. actapharmacologicasinica,2020,41(3):415.
APA	Lai Mengzhen.,Song Peiran.,Dou Dou.,Diao Yanyan.,Tong Linjiang.,...&Ding Jian.(2020).discoveryandbiologicalevaluationofn372methoxy44methylpiperazin1ylphenylamino4methyl2oxo2hpyrimido45d13oxazin14hylphenylacrylamideaspotentbrutonstyrosinekinaseinhibitors.actapharmacologicasinica,41(3),415.
MLA	Lai Mengzhen,et al."discoveryandbiologicalevaluationofn372methoxy44methylpiperazin1ylphenylamino4methyl2oxo2hpyrimido45d13oxazin14hylphenylacrylamideaspotentbrutonstyrosinekinaseinhibitors".actapharmacologicasinica 41.3(2020):415.