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.
Chen Shi  1 ,  Qian Wang  1 ,  Xuemei Liao  1 ,  Hui Ge  1 ,  Guoyong Huo  1 ,  Leduo Zhang  1 ,  Na Chen  1 ,  Xiong Zhai  1 ,  Yuan Hong  1 ,  Li Wang  1 ,  Yanan Han  1 ,  Wenbo Xiao  1 ,  Zhe Wang  1 ,  Weijun Shi  1 ,  Yu Mao  1 ,  Jianxin Yu  1 ,  Guangxin Xia  2 ,  Yanjun Liu  3
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: [email protected].
  • 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: [email protected].
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.