2. Academic Validation
  3. 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

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

  • J Med Chem. 2018 Apr 12;61(7):3166-3192. 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
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Medicine , Nankai University , 94 Weijin Road , Tianjin 300071 , China.
  • 2 State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering , Nankai University , Tianjin 300071 , China.
  • 3 Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy , West China Hospital, Sichuan University , Chengdu 610041 , China.
  • 4 State Key Laboratory of Medicinal Chemical Biology , 94 Weijin Road , Tianjin 300071 , China.
  • 5 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education , 94 Weijin Road , Tianjin 300071 , China.
PMID: 29518312 DOI: 10.1021/acs.jmedchem.8b00209
Abstract

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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