Estrone analogs as potential inhibitors targeting EGFR-MAPK pathway in non-small-cell lung cancer.

Lung cancer is the deadliest human cancer globally, with non-small-cell lung cancer (NSCLC) being the most frequent type. Epidermal growth factor receptor (EGFR), a central regulator of tumor progression is frequently overexpressed in NSCLC and is a key drug target along with its downstream pathways. Here, we describe the biological evaluation of previously synthesized estrone analogs as potent inhibitors of NCI-H226 cells. Two of the analogs, MMA307 and MM320, significantly inhibited the proliferation of NCI-H226 cells with IC 50 doses of 2.88 ± 0.21 and 9.68 ± 0.24 μM, respectively, compared with the positive control and chemotherapy, sorafenib, IC 50 of 20.62 ± 1.32 μM. Exposing NCI-H226 cells to IC 50 concentration of MMA307 and MMA320 resulted in the downregulation of EGFR and phospho-EGFR expression levels, and suppression of activated MAPK-ERK 1/2 signaling proteins; phospho-B-Raf, phospho-MEK 1/2 , and phospho-ERK 1/2 . Furthermore, the downregulation of cyclin D 1 and concomitant upregulation of phospho-cyclin D 1 and p21 waf1/cip1 were observed after the compounds' addition to NCI-H226 cells resulting in G 1 phase cell cycle arrest. MMA320 but not MMA307 downregulated the expression levels of Dyrk1B, a checkpoint kinase at the G 1 -S phase transition of the cell cycle. Additionally, molecular dynamic simulations were performed and found that MMA307 and MMA320 have higher binding affinities than sorafenib in MEK, BRAF, cyclin D 1 , and Dyrk1B (dual-specificity tyrosine phosphorylation-regulated kinase 1B). To conclude, the present study is the first to report on the antiproliferative potential of novel estrone analogs and provide evidence that MMA307 and MMA320 are promising novel lead candidates for the development of antilung cancer drugs.