Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.
ACS Chem Biol
; 15(10): 2702-2713, 2020 10 16.
Article
em En
| MEDLINE
| ID: mdl-32902249
ABSTRACT
Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos de Fenilureia
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Sulfonamidas
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Transdução de Sinais
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Inibidores de Proteínas Quinases
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Necroptose
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article