Introduction: The combination of BRAF and tyrosine kinase (TK) inhibitors has
been demonstrated to be highly effective in inhibiting tumor development and is
an approach for overcoming resistance in clinical trials. Accordingly, a novel
series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as
antiproliferative multitargeted inhibitors.
Methods: The structures of the newly synthesized compounds 9a-o were
validated using IR, NMR, MS, and elemental techniques. 9a–o were tested as
antiproliferative agents.
Results and Discussion: The results showed that the majority of the tested
compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and
9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR
and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and
9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E
inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect
on mutant EGFR (EGFRT790M), and the results showed that the tested compounds
had considerable inhibitory action. Cell cycle study and apoptosis detection
demonstrated that compound 9b exhibits cell cycle arrest at the G2/M
transition. Molecular docking simulations reveal the binding mechanism of the
most active antiproliferative agents.