Scaffold hopping derived novel benzoxazepinone RIPK1 inhibitors as anti-necroptosis agents.
Bioorg Med Chem
; 91: 117385, 2023 08 15.
Article
em En
| MEDLINE
| ID: mdl-37364415
ABSTRACT
Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis is believed to have a significant role in contributing to inflammatory diseases. Inhibiting RIPK1 has shown promise in effectively alleviating the inflammation process. In our current study, we employed scaffold hopping to develop a series of novel benzoxazepinone derivatives. Among these derivatives, compound o1 displayed the most potent antinecroptosis activity (EC50=16.17±1.878nM) in cellular assays and exhibited the strongest binding affinity to the target site. Molecular docking analyses further elucidated the mechanism of action of o1, revealing its ability to fully occupy the protein pocket and form hydrogen bonds with the amino acid residue Asp156. Our findings highlight that o1 specifically inhibits necroptosis, rather than apoptosis, by impeding the RIPK1/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL) pathway's phosphorylation, triggered by TNFα, Smac mimetic, and z-VAD (TSZ). Additionally, o1 demonstrated dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS), surpassing the protective effect observed with GSK'772.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
/
Proteína Serina-Treonina Quinases de Interação com Receptores
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Necroptose
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM