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1.
Comput Biol Chem ; 83: 107156, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31710991

RESUMEN

BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity. METHODS: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using 1H-NMR, 13C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin. RESULTS: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells. CONCLUSION: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Simulación por Computador , Diseño de Fármacos , Flavonoides/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Flavonoides/síntesis química , Flavonoides/química , Células HEK293 , Humanos , Modelos Moleculares , Estructura Molecular , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad Cuantitativa , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química
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