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Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach.

Zuni I Bassi1, Martin C Fillmore2, Afjal H Miah1

  • 1Protein Degradation DPU, Future Pipelines Discovery, GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , United Kingdom.

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|September 12, 2018
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Summary
This summary is machine-generated.

Targeting epigenetic proteins PCAF/GCN5 with proteolysis targeting chimeras (PROTACs) offers a novel anti-inflammatory strategy. PROTACs effectively degrade PCAF/GCN5, modulating inflammatory responses in immune cells.

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Area of Science:

  • Epigenetics
  • Immunology
  • Chemical Biology

Background:

  • PCAF and GCN5 are related epigenetic proteins with acetyltransferase and bromodomains.
  • These proteins play a role in immune function, as PCAF-deficient macrophages show reduced cytokine production.
  • Targeting PCAF/GCN5 is a potential therapeutic avenue for inflammatory conditions.

Purpose of the Study:

  • To investigate the role of PCAF/GCN5 in immune response.
  • To explore pharmacological strategies for targeting PCAF/GCN5.
  • To develop novel small molecules for modulating inflammatory pathways.

Main Methods:

  • Generated PCAF/GCN5 proteolysis targeting chimeras (PROTACs).
  • Assessed the impact of PCAF/GCN5 degradation on inflammatory mediator expression.
  • Utilized LPS stimulation in macrophages and dendritic cells.

Main Results:

  • PCAF-deficient macrophages had a reduced ability to produce cytokines upon LPS stimulation.
  • Chemical inhibition of PCAF/GCN5 bromodomains did not fully replicate the diminished inflammatory response.
  • PCAF/GCN5 PROTACs successfully degraded the target proteins and modulated inflammatory mediators.

Conclusions:

  • PROTACs are effective for targeting multidomain proteins like PCAF/GCN5.
  • PCAF/GCN5 degradation presents a novel therapeutic opportunity for anti-inflammatory treatments.
  • This study highlights the potential of PROTACs in modulating immune cell function.