Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach

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.
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https://hal.umontpellier.fr/hal-02284859
Contributeur : Anthony Herrada <>
Soumis le : jeudi 12 septembre 2019 - 11:34:47
Dernière modification le : vendredi 13 septembre 2019 - 01:21:19

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Zuni Bassi, Martin Fillmore, Afjal Miah, Trevor Chapman, Claire Maller, et al.. Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach. ACS Chemical Biology, American Chemical Society, 2018, 13 (10), pp.2862-2867. ⟨10.1021/acschembio.8b00705⟩. ⟨hal-02284859⟩

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