HDAC1型
化学
细胞周期蛋白依赖激酶
组蛋白脱乙酰基酶
CDK抑制剂
乙酰化
药理学
激酶
癌症研究
细胞凋亡
组蛋白
生物化学
生物
基因
细胞周期
作者
Abdusaid Saidahmatov,Jianan Li,Shihao Xu,Xiaobei Hu,Xiangqian Gao,Weijuan Kan,Lixin Gao,Jia Li,Yuqiang Shi,Sheng Li,Peipei Wang,Yubo Zhou,Xuewu Liang,Jia Li,Hong Liu
标识
DOI:10.1021/acs.jmedchem.4c00837
摘要
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4–11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4–11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4–11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
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