Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine
Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation
confers resistance to existing irreversible EGFRT790M inhibitors.
Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine,
and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell
Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear
Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory
effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking
studies were also performed on the representative typical EGFRT790M inhibitor.
Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with
EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib
(IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited
weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed
EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular
docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen
bonds and other non-bonded interactions.
Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could
be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.