Discovery of 6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine as a highly potent cyclin-dependent kinase 4/6 inhibitor for treatment of cancer

Chen Shi; Qian Wang; Xuemei Liao; Hui Ge; Guoyong Huo; Leduo Zhang; Na Chen; Xiong Zhai; Yuan Hong; Li Wang; Yanan Han; Wenbo Xiao; Zhe Wang; Weijun Shi; Yu Mao; Jianxin Yu; Guangxin Xia; Yanjun Liu

doi:10.1016/j.ejmech.2019.06.005

Discovery of 6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine as a highly potent cyclin-dependent kinase 4/6 inhibitor for treatment of cancer

Eur J Med Chem. 2019 Sep 15:178:352-364. doi: 10.1016/j.ejmech.2019.06.005. Epub 2019 Jun 4.

Authors

Chen Shi¹, Qian Wang¹, Xuemei Liao¹, Hui Ge¹, Guoyong Huo¹, Leduo Zhang¹, Na Chen¹, Xiong Zhai¹, Yuan Hong¹, Li Wang¹, Yanan Han¹, Wenbo Xiao¹, Zhe Wang¹, Weijun Shi¹, Yu Mao¹, Jianxin Yu¹, Guangxin Xia², Yanjun Liu³

Affiliations

¹ Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China.
² Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: xiagx@sphchina.com.
³ Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: liuyj@sphchina.com.

PMID: 31200237
DOI: 10.1016/j.ejmech.2019.06.005

Abstract

Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC₅₀ = 0.710/1.10 nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development.

Keywords: Antitumor; CDK4/6 inhibitors; Cell cycle; Selectivity.

MeSH terms

A549 Cells
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6