BRD3 PROTAC degrader targets H3K18ac to alleviate retinal microglia-driven uveitis

Area of Science:

• Ophthalmology
• Immunology
• Pharmacology

Background:

• Uveitis is a sight-threatening intraocular inflammation.
• Proinflammatory immune responses, particularly from retinal microglia, are key drivers of uveitis.
• The therapeutic potential of Proteolysis targeting chimera (PROTAC) targeting bromodomain and extraterminal (BET) proteins in uveitis is largely unexplored.

Purpose of the Study:

• To investigate the therapeutic effects of PROTAC D072 on experimental autoimmune uveitis.
• To determine the specific target and mechanism of action of D072 in inhibiting inflammation.

Main Methods:

• Administration of PROTAC D072 in a murine model of uveitis.
• Assessment of intraocular inflammation and microglial activation.
• Drug target verification using biochemical assays.
• Mechanistic studies involving histone modifications (H3K18ac) and gene occupancy analysis (CUT&Tag).

Main Results:

• PROTAC D072 significantly reduced intraocular inflammation and inhibited proinflammatory microglia in vivo and in vitro.
• D072 specifically degraded BRD3, with minimal impact on BRD2 and BRD4.
• BRD3 degradation led to reduced H3K18ac levels and altered gene expression profiles.
• Histone deacetylases (HDACs) were found to partially regulate H3K18ac levels post-BRD3 degradation.

Conclusions:

• PROTAC D072 is a specific BRD3 degrader effective in inhibiting proinflammatory microglia in autoimmune uveitis.
• Targeted degradation of BRD3 presents a promising therapeutic strategy for managing uveitis.