Target identification, lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors
| Autor: | Hayam M. A. Ashour, Ibrahim M. Labouta, Manal N. S. Saudi, Ahmed Hassan, Marwa H. El-Wakil |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
C-Met Stereochemistry Antineoplastic Agents 01 natural sciences Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery Tumor Cells Cultured Humans Structure–activity relationship Protein Kinase Inhibitors Molecular Biology IC50 Cell Proliferation Dose-Response Relationship Drug Molecular Structure Triazines 010405 organic chemistry Kinase Cell growth Chemistry Organic Chemistry Proto-Oncogene Proteins c-met 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Protein kinase domain Docking (molecular) Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic Chemistry. 73:154-169 |
| ISSN: | 0045-2068 |
| Popis: | 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=31.70μM). 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 0.01-1.86µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC50=4.31µM). 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. |
| Databáze: | OpenAIRE |
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