Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer.
Eur J Med Chem
; 277: 116711, 2024 Nov 05.
Article
in En
| MEDLINE
| ID: mdl-39094277
ABSTRACT
To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Non-Small-Cell Lung
/
Drug Resistance, Neoplasm
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Protein Kinase Inhibitors
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Cell Proliferation
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ErbB Receptors
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Lung Neoplasms
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Mutation
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Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
France