Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7H-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

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7H-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 ( IF 6.8 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00209
Yongtao Li ₁ , Xiaohe Luo ₁ , Qingxiang Guo ₁ , Yongwei Nie ₁ , Tianqi Wang ₁ , Chao Zhang ₁ , Zhi Huang ₁ , Xin Wang ₁ , Yanhua Liu ₁ , Yanan Chen ₁ , Jianyu Zheng ₂ , Shengyong Yang ₃ , Yan Fan _{1,

4,

5} , Rong Xiang _{1,

4,

5}

Affiliation

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-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.

中文翻译：

的发现Ñ 1-（4 - （（7-环戊基-6-（二甲基氨基甲）-7 ħ吡咯并[2,3- d ]嘧啶-2-基）氨基）苯基） - ñ 8 hydroxyoctanediamide作为一种新颖的抑制剂针对恶性肿瘤靶向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）

已经设计和合成了一系列针对CDK4 / 9和HDAC1的新型，高效，选择性抑制剂。发现了N 1-（4-（（7-环戊基-6-（二甲基氨基甲酰基）-7 H-吡咯并[2，3 - d ]嘧啶-2-基）氨基）苯基）-N 8-羟基辛二酰胺（6e）。具有优异的CDK4 / 9和HDAC1抑制活性IC _50分别为8.8、12和2.2 nM的前导化合物6e可有效诱导癌细胞系的凋亡。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在高浓度下诱导G2 / M停滞，在低浓度下诱导G0 / G1停滞，以防止癌细胞的增殖和分化。6e治疗的裸鼠乳腺癌表现出显着的抗肿瘤功效。对6e机制的见解表明，它可以通过基于CDK4 / 9和HDAC1抑制以及p53磷酸化的细胞凋亡诱导癌细胞死亡。我们的数据表明，新型化合物6e可能是有希望的癌症治疗药物。

更新日期：2018-03-08

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南