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

[INTRODUCTION] 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.

[METHODS] Ten thiourea derivatives (1-10) underwent virtual screening, were synthesized, and evaluated on EGFR-expressing cells and normal fibroblasts.

[RESULTS AND DISCUSSION] 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.

[CONCLUSION] 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.