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：

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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（C​​DK4 / 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。