期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 17, 页码 7447-7458出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00794
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)-Project MFAG [2013-N.14392]
- Progetti di Rilevante Interesse Nazionale (PRIN) [2012C5YJSK_003, 2012CTAYSY_002]
- Regione Campania under POR Campania FESR [2007-2013-O.O.2.1]
Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an in silico drug repurposing approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
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