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Published on: June 26, 2019
Estrone analogs as potential inhibitors targeting EGFR-MAPK pathway in non-small-cell lung cancer
Felix Acheampong1, Trevor Ostlund2, Mater Mahnashi3
1Verve Therapeutics, Cambridge, Massachusetts, USA.
Abstract:
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 IC50 doses of 2.88 ± 0.21 and 9.68 ± 0.24 μM, respectively, compared with the positive control and chemotherapy, sorafenib, IC50 of 20.62 ± 1.32 μM. Exposing NCI-H226 cells to IC50 concentration of MMA307 and MMA320 resulted in the downregulation of EGFR and phospho-EGFR expression levels, and suppression of activated MAPK-ERK1/2 signaling proteins; phospho-B-Raf, phospho-MEK1/2 , and phospho-ERK1/2 . Furthermore, the downregulation of cyclin D1 and concomitant upregulation of phospho-cyclin D1 and p21waf1/cip1 were observed after the compounds' addition to NCI-H226 cells resulting in G1 phase cell cycle arrest. MMA320 but not MMA307 downregulated the expression levels of Dyrk1B, a checkpoint kinase at the G1 -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 D1 , 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.
Insights
Novel estrone analogs, MMA307 and MMA320, show significant antiproliferative effects against non-small-cell lung cancer (NSCLC) cells. These compounds inhibit key signaling pathways and induce cell cycle arrest, presenting promising leads for lung cancer drug development.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Lung cancer, particularly non-small-cell lung cancer (NSCLC), is a leading cause of cancer-related mortality worldwide.
- Epidermal growth factor receptor (EGFR) signaling is frequently dysregulated in NSCLC and represents a critical therapeutic target.
- Estrone analogs are being explored for their potential anticancer properties.
Purpose of the Study:
- To evaluate the antiproliferative activity of novel estrone analogs against NSCLC cells.
- To investigate the molecular mechanisms underlying the effects of these analogs on cancer cell signaling pathways.
- To assess the binding affinities of these analogs to key target proteins involved in cell proliferation.
Main Methods:
- Biological evaluation of estrone analogs (MMA307, MMA320) using NCI-H226 NSCLC cells.
- Determination of half-maximal inhibitory concentrations (IC50) and comparison with sorafenib.
- Analysis of key signaling pathway proteins (EGFR, MAPK-ERK1/2, cyclin D1, p21, Dyrk1B) using Western blotting.
- Molecular dynamic simulations to assess binding affinities to target proteins.
Main Results:
- MMA307 and MMA320 demonstrated significant inhibition of NCI-H226 cell proliferation, with lower IC50 values than sorafenib.
- Treatment with MMA307 and MMA320 led to downregulation of EGFR and activated MAPK-ERK1/2 signaling.
- Compounds induced G1 phase cell cycle arrest through modulation of cyclin D1 and p21waf1/cip1 expression.
- MMA320 specifically downregulated Dyrk1B, a cell cycle checkpoint kinase.
- Molecular simulations indicated higher binding affinities of MMA307 and MMA320 to MEK, BRAF, cyclin D1, and Dyrk1B compared to sorafenib.
Conclusions:
- Novel estrone analogs MMA307 and MMA320 exhibit potent antiproliferative activity against NSCLC cells.
- These compounds exert their effects by inhibiting crucial oncogenic signaling pathways and inducing cell cycle arrest.
- MMA307 and MMA320 represent promising lead candidates for the development of novel anti-lung cancer therapeutics.
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