4-Pyridone-3-carboxylic acid as a benzoic acid bioisostere: Design, synthesis, and evaluation of EP300/CBP histone acetyltransferase inhibitors.
Bioorg Med Chem Lett
; 51: 128358, 2021 11 01.
Article
em En
| MEDLINE
| ID: mdl-34534674
ABSTRACT
Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Sialoglicoproteínas
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Desenho de Fármacos
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Ácido Benzoico
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Inibidores Enzimáticos
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Proteína p300 Associada a E1A
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article