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

Volynets, Galyna P.; Vdovin, Vasyl; Lukashov, S. S.; Borovykov, O. V.; Borysenko, I. P.; Gryshchenko, Andrii; Bdzhola, Volodymyr G.; Iatsyshyna, A. P.; Лукаш, Л. Л.; Bilokin, Yaroslav V.; Yarmoluk, S. M.

doi:10.2174/1573408017666210809102227

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“…The findings agreed with those obtained from the # contacts (Figure ) and in vitro assay (Table ). These interacting amino acid residues were also noted for other reported FGFR1 inhibitors such as 1-(1 H -benzimidazol-5-yl)-5-aminopyrazoles, 2-arylbenzothiazoles, and indazole 1 . The van der Waals (Δ E vdW + Δ G solv,nonpolar ) and electrostatic (Δ E elec + Δ G solv,polar ) contributions from each interacting residue of FGFR1 to the bindings of compounds 5 , 7 , and 9 were further investigated.…”

Section: Resultsmentioning

confidence: 69%

“…Of note, the top three most potent compounds including 5 , 9 , and 7 (IC 50 = 0.33, 0.50, and 0.85 nM, respectively) exhibited higher inhibitory activity than the reported FGFR1 inhibitors such as 3,5-disubstituted indolin-2-ones A13 (IC 50 = 6.99 nM), 43 3-vinyl-quinoxalin-2(1 H )-ones (IC 50 = ∼15,000–26,000 nM), 44 2-arylbenzothiazoles (IC 50 = 190–370 nM), 45 and indazole 1 (IC 50 = 100 nM). 46 Accordingly, these three compounds were selected for further in silico studies.…”

Section: Resultsmentioning

confidence: 99%

“…These interacting amino acid residues were also noted for other reported FGFR1 inhibitors such as 1-(1 H -benzimidazol-5-yl)-5-aminopyrazoles, 47 2-arylbenzothiazoles, 45 and indazole 1. 46 The van der Waals (Δ E vdW + Δ G solv,nonpolar ) and electrostatic (Δ E elec + Δ G solv,polar ) contributions from each interacting residue of FGFR1 to the bindings of compounds 5 , 7 , and 9 were further investigated. It was demonstrated that the main energy contributing to the binding of naphthoquinone–chalcone analogs against the target FGFR1 residues is the van der Waals interactions (blue line) rather the electrostatic attraction (red line) ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

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Discovery of Novel Naphthoquinone–Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling

Leechaisit,

Mahalapbutr,

Boonsri

et al. 2023

ACS Omega

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This work presents a flexible synthesis of 10 novel naphthoquinone–chalcone derivatives ( 1 – 10 ) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC 50 values in the range of 0.81–62.06 μM, especially the four most potent compounds 1 , 3 , 8 , and 9 . The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives ( 1 – 2 , 4 – 5 , and 7 – 10 ) were active FGFR1 inhibitors (IC 50 = 0.33–3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC 50 = 12.17 nM). Promisingly, compounds 5 (IC 50 = 0.33 ± 0.01 nM), 9 (IC 50 = 0.50 ± 0.04 nM), and 7 (IC 50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5 , 7 , and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone–chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.

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Section: Resultsmentioning

confidence: 69%