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Quinoxalinones as A Novel Inhibitor Scaffold for EGFR (L858R/T790M/C797S) Tyrosine Kinase: Molecular Docking,
Utid Suriya1, Panupong Mahalapbutr2, Watchara Wimonsong3
1Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Abstract:
Combating acquired drug resistance of EGFR tyrosine kinase (TK) is a great challenge and an urgent necessity in the management of non-small cell lung cancers. The advanced EGFR (L858R/T790M/C797S) triple mutation has been recently reported, and there have been no specific drugs approved for this strain. Therefore, our research aimed to search for effective agents that could impede the function of EGFR (L858R/T790M/C797S) TK by the integration of in silico and in vitro approaches. Our in-house quinoxalinone-containing compounds were screened through molecular docking and their biological activity was then verified by enzyme- and cell-based assay. We found that the four quinoxalinone-containing compounds including CPD4, CPD15, CPD16, and CPD21 were promising to be novel EGFR (L858R/T790M/C797S) TK inhibitors. The IC50 values measured by the enzyme-based assay were 3.04 ± 1.24 nM; 6.50 ± 3.02 nM,10.50 ± 1.10 nM; and 3.81 ± 1.80 nM, respectively, which are at a similar level to a reference drug; osimertinib (8.93 ± 3.01 nM). Besides that, they displayed cytotoxic effects on a lung cancer cell line (H1975) with IC50 values in the range of 3.47 to 79.43 μM. In this proposed study, we found that all screened compounds could interact with M793 at the hinge regions and two mutated residues including M790 and S797; which may be the main reason supporting the inhibitory activity in vitro. The structural dynamics revealed that the screened compounds have sufficient non-native contacts with surrounding amino acids and could be well-buried in the binding site's cleft. In addition, all predicted physicochemical parameters were favorable to be drug-like based on Lipinski's rule of five, and no extreme violation of toxicity features was found. Altogether, this study proposes a novel EGFR (L858R/T790M/C797S) TK inhibitor scaffold and provides a detailed understanding of compounds' recognition and susceptibility at the molecular level.
Insights
Researchers identified novel quinoxalinone compounds as potential inhibitors for the triple-mutated EGFR (L858R/T790M/C797S) tyrosine kinase (TK), a key challenge in non-small cell lung cancer treatment. These compounds show promising activity, offering a new therapeutic avenue.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Acquired resistance to EGFR tyrosine kinase (TK) inhibitors is a significant challenge in non-small cell lung cancer (NSCLC) management.
- The EGFR (L858R/T790M/C797S) triple mutation confers resistance to existing therapies, necessitating the development of new drugs.
- No specific drugs are currently approved for this advanced mutation.
Purpose of the Study:
- To identify novel quinoxalinone-containing compounds effective against the EGFR (L858R/T790M/C797S) triple mutation.
- To investigate the molecular mechanisms underlying the inhibitory activity of these compounds.
- To evaluate the drug-like properties and potential toxicity of the identified inhibitors.
Main Methods:
- In silico screening using molecular docking to identify potential EGFR (L858R/T790M/C797S) TK inhibitors from a library of quinoxalinone compounds.
- In vitro validation using enzyme-based and cell-based assays to determine inhibitory concentrations (IC50) and cytotoxic effects.
- Structural analysis of compound-target interactions and assessment of physicochemical properties based on Lipinski's rule of five.
Main Results:
- Four quinoxalinone compounds (CPD4, CPD15, CPD16, CPD21) demonstrated potent inhibition of EGFR (L858R/T790M/C797S) TK, with IC50 values in the nanomolar range, comparable to osimertinib.
- These compounds exhibited cytotoxic effects against the H1975 lung cancer cell line.
- Molecular docking and dynamics revealed favorable interactions with key residues (M790, S797) and the hinge region, suggesting a mechanism of action.
- Predicted physicochemical properties aligned with Lipinski's rule of five, indicating good drug-like potential.
Conclusions:
- Quinoxalinone-containing compounds represent a promising scaffold for developing novel inhibitors against the drug-resistant EGFR (L858R/T790M/C797S) triple mutation.
- The identified compounds offer a potential new therapeutic strategy for NSCLC patients with advanced EGFR mutations.
- This study provides a molecular understanding of the interaction between these inhibitors and the target, guiding future drug design.
