Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer.
机构：[1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China[2]State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin 300071, China[3]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin 300071, China[4]State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China[5]Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院
A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity. Compound 6e induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with 6e showed significant antitumor efficacy. The insight into mechanisms of 6e indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound 6e could be a promising drug candidate for cancer therapy.
基金：
Project of Science and Technology
Assistance in Developing Countries (KY201501006),
the National Natural Science Foundation of China (81470354),
and the Natural Science Foundation of Tianjin (17JCQNJC13500)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|2 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China[2]State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin 300071, China[3]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin 300071, China
推荐引用方式(GB/T 7714)：
Li Yongtao,Luo Xiaohe,Guo Qingxiang,et al.Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer.[J].Journal of medicinal chemistry.2018,61(7):3166-3192.doi:10.1021/acs.jmedchem.8b00209.
APA：
Li Yongtao,Luo Xiaohe,Guo Qingxiang,Nie Yongwei,Wang Tianqi...&Xiang Rong.(2018).Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer..Journal of medicinal chemistry,61,(7)
MLA：
Li Yongtao,et al."Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer.".Journal of medicinal chemistry 61..7(2018):3166-3192
医学