Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors.
Eur J Med Chem
; 244: 114856, 2022 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-36279692
ABSTRACT
Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 µM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 µM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.
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Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Carcinoma Pulmonar de Células não Pequenas
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Inibidores de Proteínas Quinases
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Receptores ErbB
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Compostos de Anilina
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article