2. Academic Validation
  3. Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach

Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach

  • ACS Chem Biol. 2018 Oct 19;13(10):2862-2867. doi: 10.1021/acschembio.8b00705.
Zuni I Bassi 1,  Martin C Fillmore 2,  Afjal H Miah 1,  Trevor D Chapman 3,  Claire Maller 3,  Emma J Roberts 3,  Lauren C Davis 3,  Darcy E Lewis 3,  Nicholas W Galwey 4,  Kirsty E Waddington,  Valentino Parravicini,  Abigail L Macmillan-Jones 1,  Celine Gongora 5,  Philip G Humphreys 3,  Ian Churcher,  Rab K Prinjha 3,  David F Tough 3
Affiliations

Affiliations

  • 1 Protein Degradation DPU, Future Pipelines Discovery, GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , United Kingdom.
  • 2 NCE-MD Medicinal Chemistry UK Team, R&D Platform Technology & Science, GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , United Kingdom.
  • 3 Epigenetics DPU, Immuno-Inflammation and Oncology Therapy Area, GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , United Kingdom.
  • 4 Target Sciences Statistics, R&D Target Sciences, GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , United Kingdom.
  • 5 Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier , Montpellier F-34298 , France.
PMID: 30200762 DOI: 10.1021/acschembio.8b00705
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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