Discovery of &ITN&IT1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7&ITH&IT-pyrrolo[2,3-&ITd&IT]pyrimidin-2-yl)amino)phenyl)-&ITN&IT8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase 1 (HDAC1) against Malignant Cancer
Discovery of &ITN&IT1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7&ITH&IT-pyrrolo[2,3-&ITd&IT]pyrimidin-2-yl)amino)phenyl)-&ITN&IT8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase 1 (HDAC1) against Malignant Cancer
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DOI：
10.1021/acs.jmedchem.8b00209
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发表时间：
2018-04-12
影响因子：
7.3
通讯作者：
Xiang, Rong
中科院分区：
文献类型：
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作者：
Li, Yongtao;Luo, Xiaohe;Xiang, Rong
一系列针对细胞周期蛋白依赖性激酶4/9（CDK4/9）和组蛋白去乙酰化酶1（HDAC1）的新型、高效、选择性抑制剂已被设计并合成。发现了N1 -（4 -（（7 - 环戊基 - 6 -（二甲基氨基甲酰基） - 7H - 吡咯并[2,3 - d]嘧啶 - 2 - 基）氨基）苯基） - N8 - 羟基辛二酰胺（6e）。先导化合物6e对CDK4/9和HDAC1具有出色的抑制活性，其半数抑制浓度（IC50）分别为8.8 nM、12 nM和2.2 nM，能够有效诱导癌细胞系凋亡。化合物6e的激酶谱显示出优异的选择性和特异性。化合物6e在高浓度时诱导细胞周期阻滞于G2/M期，低浓度时诱导阻滞于G0/G1期，从而阻止癌细胞的增殖和分化。用6e处理的裸鼠乳腺癌模型显示出显著的抗肿瘤疗效。对6e作用机制的深入研究表明，它可通过抑制CDK4/9和HDAC1以及使p53磷酸化，经由细胞凋亡诱导癌细胞死亡。我们的数据表明，新型化合物6e有望成为一种有前景的癌症治疗候选药物。
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)-7H-pyrrolo [2,3-d]pyrimidin-2-yl)amino)phenyl)-N8-hydroxyo ctan ediamide (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.