Discovery of N 1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)- N 8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer

作者：Yongtao Li, Xiaohe Luo, Qingxiang Guo, Yongwei Nie, Tianqi Wang, Chao Zhang, Zhi Huang, Xin Wang, Yanhua Liu, Yanan Chen, Jian‐Yu Zheng, Shengyong Yang, Yan Fan, Rong Xiang · 发表于：Journal of Medicinal Chemistry · 年份：2018 · DOI：10.1021/acs.jmedchem.8b00209 · 被引用次数：78 · 研究领域：Histone Deacetylase Inhibitors Research、Advanced Breast Cancer Therapies、Cancer Mechanisms and Therapy

A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N 1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H -pyrrolo[2,3- d ] pyrimidin-2-yl)amino)phenyl)- N 8-hydroxyoctanediamide ( 6e ) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC 50 = 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.