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Published on: June 26, 2019
Second generation Spautin-1 analogues targeting EGFR-mutant non-small cell lung cancer cells
Mathias Elsocht1, Philippe Giron2, Jacques De Grève2
1Research Group of Organic Chemistry, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
Abstract:
Treatment of advanced stage epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is often complicated by the occurrence of acquired resistance, which emphasizes the need for improved treatment options. Based on a previously reported structure-activity relationship (SAR) study of Spautin-1, which resulted in the discovery of 10a, the search for more potent analogues was envisaged through optimization of the amine substituent. Our search led to the discovery of analogue 15b, harbouring the 2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine substituent, among other potent and original analogues, with nanomolar activity towards EGFR-mutant NSCLC cells. Moreover, this compound 15b showed good selectivity for cancer cells over healthy lung epithelial cells and provides additive effects with food and drug administration (FDA) approved EGFR-tyrosine kinase inhibitors (TKIs), as proven by the co-administration of 15b with Afatinib. Altogether, we report promising lead compounds which show the potential to improve current treatment options.
Insights
New drug analogues show promise for treating advanced EGFR-mutant non-small cell lung cancer (NSCLC). Compound 15b demonstrates nanomolar activity and selectivity, offering potential new options for resistant NSCLC patients.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Acquired resistance complicates treatment for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
- Improved therapeutic strategies are crucial for overcoming treatment resistance in NSCLC.
Purpose of the Study:
- To discover novel, more potent analogues of Spautin-1 for EGFR-mutant NSCLC.
- To optimize analogues through modification of the amine substituent to enhance efficacy and selectivity.
Main Methods:
- Structure-activity relationship (SAR) study of Spautin-1 derivatives.
- Synthesis and evaluation of novel analogues, including compound 15b.
- Assessment of compound activity against EGFR-mutant NSCLC cells and selectivity over healthy cells.
Main Results:
- Discovery of analogue 15b with nanomolar activity against EGFR-mutant NSCLC cells.
- Compound 15b exhibited significant selectivity for cancer cells over healthy lung epithelial cells.
- Additive effects observed when 15b was co-administered with FDA-approved EGFR-tyrosine kinase inhibitors (TKIs) like Afatinib.
Conclusions:
- Novel analogues, particularly 15b, show significant potential as lead compounds for improved NSCLC treatment.
- These compounds offer a promising avenue for overcoming acquired resistance in EGFR-mutant NSCLC.
- The findings support the development of new therapies targeting resistant NSCLC.
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