Virtual Screening and Biological Evaluation of T22306 as a Potent Third-generation EGFR Inhibitor for NSCLC Treatment.

objectivesAccording to the data, mutations in EGFR-related genes are the main cause of Non-Small Cell Lung Cancer (NSCLC), necessitating the development of new drug constructs for EGFR-TKIs particularly important. This study aimed to screen potential third-generation EGFR-TKIs to address the emerging drug resistance challenges in NSCLC.

methodsIn this study, virtual screening, molecular dynamics modeling, and bioactivity evaluation were carried out to find a potential EGFR inhibitor that could overcome the L858R/T790M mutation. At first, 12 potential compounds were screened step by step from about 250,000 structures by virtual screening. These 12 compounds were subjected to MTT antitumor activity evaluation and kinase inhibition assay to select compounds with strong antiproliferative effects on cancer cells. Then, the preferred compounds were subjected to time-dependent assay, scratch assay, AO staining assay, and hemolysis assay. Finally, the preferred compound was subjected to molecular docking and molecular dynamics simulation with 5HG7 protein.

resultThe IC50 of T22306 on H1975 cells was 9.17 μM. In further kinase evaluation, the kinase inhibition of EGFR

conclusionIn this study, we rapidly screened potential compounds against NSCLC with the help of virtual screening technology. Further in vitro experiments demonstrated that T22306 successfully overcame the L858R/T790M mutation and could be a potential epidermal growth factor receptor inhibitor.