Small-molecule allosteric inhibitors of GPX4.
Cell Chem Biol
; 29(12): 1680-1693.e9, 2022 12 15.
Article
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| MEDLINE
| ID: mdl-36423641
ABSTRACT
Encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos