Thiourea Derivatives for the Potential Treatment of Lung Cancer via the Inhibition of EGFR and Efflux Pumps: Synthesis, In Silico, and In Vitro Studies.

The overexpression and/or mutations of Epidermal Growth Factor Receptor (EGFR) are associated with the progression of several cancers. Thiourea derivatives have emerged as promising compounds to target EGFR for cancer treatment. Ten thiourea derivatives (1-10) underwent virtual screening, were synthesized, and evaluated on EGFR-expressing cells and normal fibroblasts. Compound 3 had the highest binding affinity towards HER1 and HER2 (EGFR family) with the Lowest Binding Energy (LBE) values of -9.6 and -10.9 kcal/mol, respectively. Against lung cancer cells, H69 and H2073 cells, compound 3 had IC50 values of 3.68 and 2.48 μM, respectively, with a selectivity index greater than 25 on both cancer cells. A combination index value of 1.0 (additive effect) was achieved on both cell lines when compound 3 was combined with Doxorubicin (DOX). The cytotoxic effect of compound 3 may also be driven via a non-mitochondrial pathway, as elucidated by the JC-1 mitochondrial assay. The enhancement of DOX toxicity against H69 cells (initial IC50 value was 0.6 μM) by the addition of 0.1 and 1 μM of compound 3 to reach an IC50 values of 0.27 and 0.04 μM, respectively, may be driven via the inhibitory effect of compound 3 on efflux pumps, such as ABCC1 and RALBP1 (LBE values of -9.2 and -8.41 kcal/mol, respectively), known as reasons for DOX resistance and their expression in H69 cells. Compound 3 has shown to have cytotoxic effects against EGFR-expressing lung cancer cells, causes an additive effect with conventional chemotherapy, and may be used to treat multi-drug-resistant cancers.