2. Academic Validation
  3. 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

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

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.

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