2. Academic Validation
  3. Second generation Spautin-1 analogues targeting EGFR-mutant non-small cell lung cancer cells

Second generation Spautin-1 analogues targeting EGFR-mutant non-small cell lung cancer cells

  • Bioorg Med Chem Lett. 2023 Jan 1:79:129066. doi: 10.1016/j.bmcl.2022.129066.
Mathias Elsocht 1,  Philippe Giron 2,  Jacques De Grève 3,  Steven Ballet 4
Affiliations

Affiliations

  • 1 Research Group of Organic Chemistry, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: Mathias.Elsocht@vub.be.
  • 2 Laboratory of Medical and Molecular Oncology and Center of Medical Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Philippe.Giron@vub.be.
  • 3 Laboratory of Medical and Molecular Oncology and Center of Medical Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Jacques.DeGreve@uzbrussel.be.
  • 4 Research Group of Organic Chemistry, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: Steven.Ballet@vub.be.
PMID: 36410591 DOI: 10.1016/j.bmcl.2022.129066
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.

Keywords

EGFR; Non-small cell lung cancer; Quinazolinamines; USP13.

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