Identification of Novel Indazole-based Inhibitors of Fibroblast Growth Factor Receptor 1 (FGFR1)

Title:Identification of Novel Indazole-based Inhibitors of Fibroblast Growth Factor Receptor 1 (FGFR1)

Volume: 17 Issue: 3

Author(s): Galyna Volynets*, Vasyl Vdovin, Sergiy Lukashov, Oleksiy Borovykov, Iryna Borysenko, Andrii Gryshchenko, Volodymyr Bdzhola, Anna Iatsyshyna, Lyubov Lukash, Yaroslav Bilokin and Sergiy Yarmoluk

Affiliation:

• Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv,Ukraine

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

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.

Cite this article as:

Volynets Galyna*, Vdovin Vasyl, Lukashov Sergiy, Borovykov Oleksiy, Borysenko Iryna, Gryshchenko Andrii, Bdzhola Volodymyr, Iatsyshyna Anna, Lukash Lyubov, Bilokin Yaroslav and Yarmoluk Sergiy, Identification of Novel Indazole-based Inhibitors of Fibroblast Growth Factor Receptor 1 (FGFR1), Current Enzyme Inhibition 2021; 17 (3) . https://dx.doi.org/10.2174/1573408017666210809102227

DOI https://dx.doi.org/10.2174/1573408017666210809102227	Print ISSN 1573-4080
Publisher Name Bentham Science Publisher	Online ISSN 1875-6662