体内
化学
激酶
细胞凋亡
癌症研究
药理学
离体
药代动力学
细胞周期蛋白
细胞培养
调节器
体外
细胞周期
生物化学
生物
基因
生物技术
遗传学
作者
Xinren Wang,Xiaoyue Liu,Jiankang Huang,Chenhe Liu,Hongmei Li,Cong Wang,Qianqian Hong,Lei Yan,Jiawei Xia,Ziheng Yu,Ruinan Dong,Junyu Xu,Zhenlin Tu,Chunqi Duan,Shuwen Li,Tao Lü,Weifang Tang,Yadong Chen
标识
DOI:10.1016/j.ejmech.2022.114461
摘要
Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.
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