Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
14 Dec 2019
14 Dec 2019
Historique:
received:
12
07
2019
accepted:
03
10
2019
entrez:
21
12
2019
pubmed:
21
12
2019
medline:
21
12
2019
Statut:
epublish
Résumé
Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.
Identifiants
pubmed: 31857889
doi: 10.1039/c9sc03445e
pii: c9sc03445e
pmc: PMC6886544
doi:
Types de publication
Journal Article
Langues
eng
Pagination
10789-10801Informations de copyright
This journal is © The Royal Society of Chemistry 2019.
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