Loading...
4-Aryl-N-phenylpyrimidin-2-amines targeting EGFR-tyrosine kinase attenuated EGFR-expressing cell lines
Author(s)
Tabtimmai, Lueacha
Supakun, Prapasri
Toviwek, Borvornvat
Jiwacharoenchai, Nattanan
Kiriwan, Duangnapa
Aiebchun, Thitinan
Gleeson, M. Paul
Choowongkomon, Kiattawee
Date Issued
August 1, 2022
Type
Article
Abstract
Target therapies have been widely developed to combat various diseases and cancer. Epidermal Growth Factor Receptor is still a currently therapeutic target for solid tumor. Aberration of EGFR activity or expression reflect disease progression and poor prognosis. Recently, several newly synthesized 4-aryl-N-phenylpyrimidin-2-amines with some modifications at R2 selectively elicited cytotoxicity against A549. Therefore, harboring EGFR expression would be reasonable for the assessment. Herein, the 4-aryl-N-phenylpyrimidin-2-amines derivatives; N-(3-{[4-(4-methoxyphenyl) pyrimidin-2-yl]amino}phenyl), 3-{[4-(3-methoxyphenyl) pyrimidin-2-yl] amino}benzene-1-sulfonamide. (13g), methanesulfonamide (13c), 3-[(4-phenylpyrimidin-2-yl)amino] benzene-1-sulfonamide (13f) and 3-(benzene-1-sulfonamide) (5) were selected as promising derivatives for targeted-EGFR analysis. Kinase enzymatic-based assay exhibited IC50 values of 5.61, 31.92, 73.80 and 0.79 nM of each derivative, respectively whilst 41.50 nM of Gefitinib. Molecular docking deciphered the mode of binding of each derivative in ATP-binding site greater than gefitinib. Although, (13g) demonstrated the highest binding free energy among the other but not in ATP-binding site as the others does that related to its IC50 values. (13c), (13f), and (5) therefore were subjected for cell-based analysis. A549 and A431 were used as wtEGFR-expressing cells for cell-based assay. (13c), (13f), and (5) had high toxicity towards in both cells while (5) had much more toxicity on A431. (13c), (13f) and (5) not only induced apoptosis in a dose-dependent manner but reduced clonogenic formation greater than gefitinib. Migration of EGF-stimulated A431 was significantly delayed by the compounds over time but they could not delay EGF-stimulated A549 migration. Taken together, (13c), (13f) and (5) would be a newly synthesized derivative by targeting wtEGFR-expressing cells that attenuated EGFR-driven cancer hallmark leading to targeted therapy development.
Citation
European Journal of Medicinal Chemistry Reports, 5, 2022