Background:
Overactivity of fibroblast growth factor receptor 1 (FGFR1) is associated with various tumors, particularly breast cancer, prostate cancer, non-small-cell lung carcinoma, myeloproliferative diseases, which makes this protein kinase a promising therapeutic target for anticancer therapy.
Objective:
The main aim of this study is to identify novel FGFR1 inhibitors.
Method:
In order to find FGFR1 inhibitors, virtual screening experiments were performed using AutoDock software. Best-scored compounds were tested in vitro using P32 radioactive kinase assay.
Results:
Small-molecular inhibitors of protein kinase FGFR1 were identified among indazole derivatives. The most active compound [3-(3,4-dichloro-phenyl)-1H-indazol-5-yl]-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)-amine (1) inhibits FGFR1 with IC50 value of 100 nM. According to molecular docking results, this compound interacts simultaneously with adenine- and phosphate-binding regions of protein kinase FGFR1. The structure-activity relationships have been investigated and binding mode has been predicted.
Conclusion:
The compound 1 can be used for further structural optimization and biological research.
To synthesize the novel purine bioisosteres -indazole derivatives and evaluate inhibitory activity of these compounds towards CK2 in the in vitro system. Methods. Chemical synthesis, 1 H and 13 C NMR spectroscopy, LC-MS method, determination of residual enzyme activity using ATP consumption tests with a luciferase Kinase-Glo® luminescent kinase assay. Results. Known synthetic methods of indazole chemistry were originally applied to the synthesis of 3-aryl-indazole-7-carboxylic acids. Conditions of cross-coupling of 3-bromo-indazole derivatives with arylboronic acids were substantially improved. 3-aryl-indazole 5-and 7-carboxylic acids have shown IC 50 in a range 3.1-6.5 μM in luciferase luminescent kinase assay. Conclusions. The synthesis of 3-aryl-indazole-7-carboxylic acids has been developed. Novel inhibitors of the protein kinase CK2 among indazole derivatives have been identified among the 3-aryl-indazole 5-and 7-carboxylic acids. It has been shown the crucial impact of carboxyl group on the inhibitory activity of studied compounds.
K e y w o r d s:Indazole, chemical synthesis, luciferase luminescent kinase assay, protein kinase inhibitor, protein kinase CK2.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.