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Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies

文献类型：期刊论文

作者Saidahmatov, Abdusaid4,5; Li, Jianan3; Xu, Shihao4,5; Hu, Xiaobei2,5; Gao, Xiangqian3; Kan, Weijuan5; Gao, Lixin5; Li, Cong5; Shi, Yuqiang5; Sheng, Li5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-08-23
卷号67期号:17页码:15220-15245
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00837
通讯作者Liang, Xuewu(liangxuewu0714@126.com) ; Li, Jia(jli@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要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.
WOS关键词HDAC ; RESISTANCE
资助项目National Natural Science Foundation of China[21907102] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[22377138] ; National Natural Science Foundation of China[22337003] ; Alliance of International Science Organizations (ANSO) ; Lingang Laboratory[LG202103-02-07] ; Lingang Laboratory[LG-QS-202205-09]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001298175600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/313080]  
专题新药研究国家重点实验室
通讯作者Liang, Xuewu; Li, Jia; Liu, Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Saidahmatov, Abdusaid,Li, Jianan,Xu, Shihao,et al. Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(17):15220-15245.
APA Saidahmatov, Abdusaid.,Li, Jianan.,Xu, Shihao.,Hu, Xiaobei.,Gao, Xiangqian.,...&Liu, Hong.(2024).Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.JOURNAL OF MEDICINAL CHEMISTRY,67(17),15220-15245.
MLA Saidahmatov, Abdusaid,et al."Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies".JOURNAL OF MEDICINAL CHEMISTRY 67.17(2024):15220-15245.

入库方式： OAI收割

来源：上海药物研究所

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