Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist.
Cell Death Dis
; 14(8): 555, 2023 08 24.
Article
em En
| MEDLINE
| ID: mdl-37620300
ABSTRACT
Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína Serina-Treonina Quinases de Interação com Receptores
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Vemurafenib
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Necroptose
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article