Target identification,lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors |
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| Institution: | 1. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;3. High Magnetic Field Laboratory, Chinese Academy of Sciences, P.O. Box 1110, Hefei, Anhui 230031, PR China;4. University of Science and Technology of China, Hefei, Anhui 230036, PR China;1. Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China;2. Chong Qing Yaopharma CO., LTD, Chongqing 401121, PR China;1. Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;2. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;1. School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China;2. Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China |
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| Abstract: | In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC50 = 31.70 μM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure-activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC50 values in the range 0.01–1.86 µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC50 = 4.31 µM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives. |
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| Keywords: | Target fishing Lead optimization c-Met kinase Docking 1 2 4-Triazines Antitumor agents |
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