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

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   Pages 1 - 5 ( 5 )

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.

Affiliation:

Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv, OTAVA Ltd., 400 Applewood Crescent, Unit 100, Vaughan, Ontario, L4K 0C3 , Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., 03143, Kyiv



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