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

Yongtao Li; Xiaohe Luo; Qingxiang Guo; Yongwei Nie; Tianqi Wang; Chao Zhang; Zhi Huang; Xin Wang; Yanhua Liu; Yanan Chen; Jianyu Zheng; Shengyong Yang; Yan Fan; Rong Xiang

doi:10.1021/acs.jmedchem.8b00209

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. Epub 2018 Mar 23.

Authors

Yongtao Li¹, Xiaohe Luo¹, Qingxiang Guo¹, Yongwei Nie¹, Tianqi Wang¹, Chao Zhang¹, Zhi Huang¹, Xin Wang¹, Yanhua Liu¹, Yanan Chen¹, Jianyu Zheng², Shengyong Yang³, Yan Fan^{1

4

5}, Rong Xiang^{1

4

5}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Cell Cycle Checkpoints / drug effects
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Female
Histone Deacetylase 1 / antagonists & inhibitors*
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / pharmacokinetics
Histone Deacetylase Inhibitors / pharmacology*
Humans
Male
Mice
Mice, Inbred BALB C
Models, Molecular
Phosphorylation / drug effects
Structure-Activity Relationship
Substrate Specificity
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Tumor Suppressor Protein p53
CDK4 protein, human
CDK9 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 9
Histone Deacetylase 1