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J Med Chem. 2018 Apr 12;61(7):3166-3192. doi: 10.1021/acs.jmedchem.8b00209. Epub 2018 Mar 23.

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.

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Department of Medicinal Chemistry, School of Medicine , Nankai University , 94 Weijin Road , Tianjin 300071 , China.
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering , Nankai University , Tianjin 300071 , China.
Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy , West China Hospital, Sichuan University , Chengdu 610041 , China.
State Key Laboratory of Medicinal Chemical Biology , 94 Weijin Road , Tianjin 300071 , China.
2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education , 94 Weijin Road , Tianjin 300071 , China.


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.

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