Exploring Quinoxalinone Derivatives as Promising Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors for Cancer Therapy
Authors:   Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, Bangkok, 10900 Thailand, Jiwacharoenchai Nattanan , Kiriwan Duangnapa ,   Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, Bangkok, 10900 Thailand, Tabtimmai Lueacha ,   Department of Biotechnology, Faculty of Applied Science, King Mongkut University of North Bangkok, Bangkok, 10800 Thailand, Seetaha Supaphorn ,   Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900 Thailand, Yotphan Sirilata ,   Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand, Suwattanasophon Chonticha ,   Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, 1010, Austria, Choowongkomon Kiattawee ,   Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, Bangkok, 10900 Thailand,   Department of Biotechnology, Faculty of Applied Science, King Mongkut University of North Bangkok, Bangkok, 10800 Thailand,   Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900 Thailand,   Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900 Thailand
Published: May 2024

E GFR plays an extensive role in the signaling pathway such as proliferation, migration, invasion. However, the malfunctioning of the epidermal growth factor receptor (EGFR) is a crucial factor in cancer progression. The search for new kinase inhibitors is necessary due to the evolving nature of diseases and the emergence of resistant strains, prompting the need for novel compounds that can effectively target and inhibit specific kinases for therapeutic purposes. This study explores quinoxalinone derivatives, comprised of benzene and pyrazine aromatic rings, as novel potential EGFR kinase inhibitors for cancer therapy, fulfilling an essential need in targeted cancer treatments. We utilized molecular docking to examine 46 synthesized quinoxalinone derivatives for their interaction with the tyrosine kinase domain of EGFR. Fifteen compounds exhibited strong binding affinities. Notably, LS3c, MN333, and MN343 displayed significant inhibitory effects on A431 cells with half-maximum inhibitory concentration (IC50) values comparable to gefitinib, erlotinib, and afatinib in enzymatic kinase assays. Subsequent experiments revealed that LS3c and MN343 effectively inhibit EGFR-expressing cell lines with low hepatotoxicity. MN343, the most potent compound, was selected for molecular dynamic simulation to understand its interaction with the tyrosine kinase of EGFR. To investigate the interaction between MN343 and EGFR’s tyrosine kinase, MM-PBSA analysis identified key residues (L694, V702, L768, M769, and L820) crucial for interaction, highlighting the potential of MN343 as a clinical EGFR tyrosine kinase inhibitor. The need for discovering new kinase inhibitors arises from the dynamic nature of diseases and the appearance of resistant strains, emphasizing the requirement for innovative compounds capable of targeting and inhibiting specific kinases effectively for therapeutic applications.