Modified pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as EGFRWT and EGFRT790M inhibitors: Design, synthesis, and anti-cancer evaluation

Abstract

This study reports design and synthesis of thirteen pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as EGFR inhibitors. The antiproliferation activities were tested for all compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines using doxorubicin as a reference. Compounds 6a, 6b, 7a, and 7b, which displayed the highest inhibitory percentage against all cell lines, were selected for further IC50 screening using erlotinib as a reference. Next, the four compounds (6a, 6b, 7a, and 7b) were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 7a showed remarkable inhibitory activity against EGFRWT and EGFRT790M with IC50 values of 0.029 and 0.055 µM, respectively in comparison with the reference drug, erlotinib (IC50 = 0.051 and 0.094 µM). Further mechanistic studies revealed the ability of compound 7a to arrest the cell cycle at pre-G1 and S phases and boosts the total apoptosis by 21.82-fold. In addition, molecular docking analysis was utilized to explain the action modes of the compounds and the EGFR kinases (wild and mutant types) that they target.