Structure-activity relationships of novel quinazoline derivatives with high selectivity for HER2 over EGFR.
Arch Pharm Res
; 45(3): 123-141, 2022 Mar.
Article
em En
| MEDLINE
| ID: mdl-35314953
ABSTRACT
The gene amplification of human epidermal growth factor receptor 2 (HER2) plays an essential role in the proliferation and progression of several cancers. However, HER2 inhibitors such as lapatinib strongly suppress wild-type EGFR, resulting in severe adverse effects. Therefore, there is an unmet need for highly selective HER2 inhibitors. In this study, we describe the design and synthesis of novel quinazoline derivatives that exhibit enhanced selectivity for HER2 over wild-type EGFR. Structure-activity relationship analysis indicated that the selectivity for HER2 over EGFR depends on the aniline moiety at C-4 and the substituents at C-6 in the quinazoline derivatives. Compound 7c with an IC50 of 8 nM for HER2 exhibited significantly higher selectivity for HER2 over EGFR, with a 240-fold improvement over lapatinib. In addition, the synthesized compounds exhibited anti-proliferative activity in the nanomolar range against SKBR3, a human breast cancer cell line that overexpresses HER2.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article