Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently.
J Am Chem Soc
; 141(51): 20407-20415, 2019 12 26.
Article
em En
| MEDLINE
| ID: mdl-31841309
ABSTRACT
GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. Although most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently the protein's catalytic selenocysteine residue, the discovery and mechanistic elucidation of structurally diverse GPX4-inhibiting molecules have uncovered novel electrophilic warheads that bind and inhibit GPX4. Here, we report our discovery that diacylfuroxans can act as masked nitrile oxide prodrugs that inhibit GPX4 covalently with unique cellular and biochemical reactivity compared to existing classes of GPX4 inhibitors. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also expand the collection of reactive groups capable of targeting GPX4.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxidiazóis
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Óxidos
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Inibidores Enzimáticos
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Fosfolipídeo Hidroperóxido Glutationa Peroxidase
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Nitrilas
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article