Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach.
ACS Chem Biol
; 13(10): 2862-2867, 2018 10 19.
Article
em En
| MEDLINE
| ID: mdl-30200762
ABSTRACT
P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. However, by generating the first PCAF/GCN5 proteolysis targeting chimera (PROTAC), we identify small molecules able to degrade PCAF/GCN5 and to potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells. Our data illustrate the power of the PROTAC approach in the context of multidomain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Piridazinas
/
Benzoatos
/
Fatores de Transcrição de p300-CBP
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article