Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR including the T790M/L858R mutant |
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| Affiliation: | 1. College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China;2. Beijing Dalitai Pharmaceutical Technology Co., Ltd, Beijing 100176, China;3. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China;1. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea;2. Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea;5. Department of Biomedical Engineering, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea;6. Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea;7. Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, South Korea;1. College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China;2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China;3. Jiangsu Key Laborotary of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, PR China;1. College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China;2. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China;3. Beijing Dalitai Pharmaceutical Technology Co. Ltd, Beijing 100176, China;1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China |
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| Abstract: | A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFRwt and some showed moderate to excellent potency against EGFRT790M/L858R mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFRwt were less than 50 nM, and those of six compounds were less than 10 nM. The IC50 values of eleven compounds against EGFRT790M/L858R were less than 100 nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFRwt (IC50 = 2.0 nM) and EGFRT790M/L858R (IC50 = 6.9 nM). Compounds with excellent inhibitory activities against EGFRwt and EGFRT790M/L858R kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation. |
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| Keywords: | EGFR inhibitors Lung cancer T790M/L858R mutation Quinazoline |
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