Modulating PCAF/GCN5 immune cell function through a PROTAC approach.
ACS chemical biology(2018)
摘要
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 multi-domain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.
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关键词
pcaf/gcn5 immune cell function,protac approach
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