In silico design, synthesis and activity of potential drug-like chrysin scaffold-derived selective EGFR inhibitors as anticancer agents

Abstract

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.

Keywords: Chrysin derivatives; Cytotoxicity; Design; Docking; Mammosphere forming ability; Pharmacophores; Synthesis.