Discovery of <i>N</i>-substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer
Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC. By employing a combination of <i>in silico</i> drug repurposing and structure-based structure-activity relationship (SAR) studies, we identified and developed novel c-MET/SMO-targeting agents with antiproliferative activity against first- as well as third-generation EGFR-TKI-resistant NSCLC cells suggesting a synergistic effect arising from the simultaneous inhibition of c-MET and SMO.
Authors
- Floriana Morgillo (ORCID: https://orcid.org/0000-0002-9167-323X)
- Sabrina Taliani
- Maria Letizia Trincavelli (ORCID: https://orcid.org/0000-0001-8124-977X)
- Carminia Maria Della Corte
- Giorgio Amendola (ORCID: https://orcid.org/0000-0003-4271-5031)
- Stefano Tomassi (ORCID: https://orcid.org/0000-0003-3152-4467)
- Emma Baglini (ORCID: https://orcid.org/0000-0002-8378-4052)
- Fortunato Ciardiello (ORCID: https://orcid.org/0000-0002-4661-5540)
- Elisabetta Barresi (ORCID: https://orcid.org/0000-0002-9814-7195)
- Sandro Cosconati (ORCID: https://orcid.org/0000-0002-8900-0968)
- Federico Da Settimo (ORCID: https://orcid.org/0000-0002-7897-7917)
- Salvatore Di Maro (ORCID: https://orcid.org/0000-0002-9286-4433)
- Anna Messere (ORCID: https://orcid.org/0000-0003-4310-9447)
- Michele Roggia (ORCID: https://orcid.org/0009-0009-3860-2502)
- Benito Natale
- Caterina De Rosa (ORCID: https://orcid.org/0000-0001-6540-0708)
- Luisa Amato (ORCID: https://orcid.org/0009-0005-6511-8071)
Institutions
- University of Pisa (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Istituto di Fisiologia Clinica (IT)
- National Research Council (IT)
- Link Campus University (IT)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1039/d4md00553h
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Università di Pisa
- Università degli Studi della Campania Luigi Vanvitelli