C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function.
Cell Chem Biol
; 31(7): 1363-1372.e8, 2024 Jul 18.
Article
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| MEDLINE
| ID: mdl-38917791
ABSTRACT
Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Cromatina
/
Receptores Citoplasmáticos y Nucleares
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Carioferinas
/
Proteína p300 Asociada a E1A
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Proteína Exportina 1
Límite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos