Discovery of Anilino-1,4-naphthoquinones as Potent EGFR Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Comprehensive Molecular Modeling
2
Issued Date
2022-05-31
Resource Type
eISSN
24701343
Scopus ID
2-s2.0-85131689000
Journal Title
ACS Omega
Volume
7
Issue
21
Start Page
17881
End Page
17893
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Omega Vol.7 No.21 (2022) , 17881-17893
Suggested Citation
Mahalapbutr P., Leechaisit R., Thongnum A., Todsaporn D., Prachayasittikul V., Rungrotmongkol T., Prachayasittikul S., Ruchirawat S., Prachayasittikul V., Pingaew R. Discovery of Anilino-1,4-naphthoquinones as Potent EGFR Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Comprehensive Molecular Modeling. ACS Omega Vol.7 No.21 (2022) , 17881-17893. 17893. doi:10.1021/acsomega.2c01188 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/84088
Title
Discovery of Anilino-1,4-naphthoquinones as Potent EGFR Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Comprehensive Molecular Modeling
Other Contributor(s)
Abstract
Epidermal growth factor receptor (EGFR) has been recognized as one of the attractive targets for anticancer drug development. Herein, a set of anilino-1,4-naphthoquinone derivatives (3-18) was synthesized and investigated for their anticancer and EGFR inhibitory potentials. Among all tested compounds, three derivatives (3, 8, and 10) were selected for studying EGFR inhibitory activity (in vitro and in silico) due to their most potent cytotoxic activities against six tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, MDA-MB-231, and T47D; IC50values = 1.75-27.91 μM), high selectivity index (>20), and good predicted drug-like properties. The experimental results showed that these three promising compounds are potent EGFR inhibitors with nanomolar IC50values (3.96-18.64 nM). Interestingly, the most potent compound 3 bearing 4-methyl substituent on the phenyl ring displayed 4-fold higher potency than the known EGFR inhibitor, erlotinib. Molecular docking, molecular dynamics simulation, and MM/GBSA-based free energy calculation revealed that van der Waals force played a major role in the accommodations of compound 3 within the ATP-binding pocket of EGFR. Additionally, the 4-CH3moiety of the compound was noted to be a key chemical feature contributing to the highly potent EGFR inhibitory activity via its formations of alkyl interactions with A743, K745, M766, and L788 residues as well as additional interactions with M766 and T790.