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

• Published in: European journal of medicinal chemistry 2019-09, Vol.178, p.352-364
• Main Authors: Shi, Chen, Wang, Qian, Liao, Xuemei, Ge, Hui, Huo, Guoyong, Zhang, Leduo, Chen, Na, Zhai, Xiong, Hong, Yuan, Wang, Li, Han, Yanan, Xiao, Wenbo, Wang, Zhe, Shi, Weijun, Mao, Yu, Yu, Jianxin, Xia, Guangxin, Liu, Yanjun
• Format: Article
• Language: English
• Subjects: Antitumor; CDK4/6 inhibitors; Cell cycle; Selectivity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.06.005

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. [Display omitted] •Compound 3c exhibited high potency on CDK4 and CDK6.•Compound 3c showed high selectivity over a variety of other kinases.•Compound 3c possessed desirable antiproliferative activities.•Compound 3c had excellent metabolic properties and good pharmacokinetic profiles.•Compound 3c reduced tumor growth on MCF-7, Colo-205, and A549 xenograft models.