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

• 来源期刊: 中国药理学报（英文版）
• 关键词: B cell receptor Bruton's tyrosine kinase ibrutinib small-molecule inhibitor B cell malignancies
• 年，卷（期）: 2020,（3）
• 页码范围: 415-422
• 页数: 8页
• 语种: 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 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 ICso 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.