Abstract

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.

Methods: 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-1Hcyclopenta[ 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: Compound 1 can be used for further structural optimization and biological research.

Keywords: Fibroblast growth factor receptor 1, FGFR1, molecular docking, kinase assay, inhibitor, indazole.