Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists.
Bioorg Med Chem Lett
; 34: 127676, 2021 02 15.
Article
em En
| MEDLINE
| ID: mdl-33166687
ABSTRACT
We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Desenho de Fármacos
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Proteínas Inibidoras de Apoptose
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Antineoplásicos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article