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
| Autor: | Jianxin Yu, Shi Chen, Huo Guoyong, Na Chen, Li Wang, Xia Guangxin, Liao Xuemei, Liu Yanjun, Zhai Xiong, Xiao Wenbo, Weijun Shi, Mao Yu, Leduo Zhang, Wang Qian, Zhe Wang, Han Yanan, Ge Hui, Yuan Hong |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Antineoplastic Agents 01 natural sciences Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Animals Humans Imidazole Potency Protein Kinase Inhibitors Cell Proliferation 030304 developmental biology Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Cyclin-dependent kinase 4 Chemistry Kinase Organic Chemistry Cyclin-Dependent Kinase 4 Cancer Cyclin-Dependent Kinase 6 Neoplasms Experimental General Medicine medicine.disease 0104 chemical sciences A549 Cells MCF-7 Cells biology.protein Amine gas treating Drug Screening Assays Antitumor Selectivity Isopropyl |
| Zdroj: | European Journal of Medicinal Chemistry. 178:352-364 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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