Investigation on LASSBio-1971 and LASSBio-1974 Cellular Cytotoxic Mechanism and Their Comparative DMPK Profile

Due to the arising of clinically relevant resistant EGFR-related phenotype through innovative mechanisms, mainly EGFR_L858R/T790M, the emergence of novel molecules with dual or multi-target affinity has presented a promising alternative to overcoming these resistance mechanisms. This study aimed to evaluate synthetic acrylamide quinoxaline derivatives against NSCLC cell lines with different overexpressed EGFR mutations and compare their DMPK profile. The biological activity of LASSBio-1971 and LASSBio-1974 was assessed through cytotoxicity (MTT and Sulforhodamine B assays), apoptosis induction, EGFR inhibition, cell cycle analysis (flow cytometry), immunofluorescence microscopy, cell membrane permeability (PAMPA assay), and metabolic stability in rat liver microsomes. LASSBio-1971 exhibited promising EGFR inhibition with favorable in vitro pharmacokinetic (PK) properties, including high gastrointestinal and blood-brain barrier permeability. LASSBio-1974 demonstrated nonselective mechanism inhibiting EGFR and mitotic machinery leading to apoptosis and cell cycle arrest at different phases. LASSBio-1971 and LASSBio-1974 emerge as EGFR inhibitors with equipotent cytotoxic effects on human NSCLC lines and different in PK profile. Further studies should be conducted with LASSBio-1974 to prove and understand its antimicrotubule action.