# Selective CBP/EP300 Bromodomain Inhibitors: Novel Epigenetic Tools to Counter TNF-α-Driven Inflammation

## TL;DR

This study introduces new epigenetic inhibitors that reduce inflammation by targeting CBP/EP300 bromodomains, showing promise for treating autoimmune diseases like rheumatoid arthritis.

## Contribution

A novel class of selective CBP/EP300 bromodomain inhibitors was developed and shown to reduce TNF-α-driven inflammation in preclinical models.

## Key findings

- The inhibitors reduced TNF-α-driven cytokine expression in vitro by blocking NFκB signaling.
- In vivo, BRD inhibition decreased cytokine secretion and immune cell migration in a murine model.
- The inhibitors are non-cytotoxic and offer a potential complementary therapy for TNF-α-mediated inflammatory conditions.

## Abstract

Tumor necrosis factor α (TNF-α) is a central
driver
of inflammation in autoimmune conditions such as Crohn’s disease
and rheumatoid arthritis (RA). Targeting epigenetic regulators involved
in cytokine expression holds therapeutic promise, yet the precise
role of the CBP/EP300 bromodomains (BRDs) in modulating immune responses
remains poorly understood. Here, we introduce a distinct class of
selective CBP/EP300-BRD inhibitors based on a unique 3-methylcinnoline
acetyl-lysine mimic, identified through high-throughput fragment docking.
These inhibitors significantly reduce TNF-α-driven cytokine
expression in vitro by blocking NFκB signaling
in immune cells. In vivo, BRD inhibition led to a
robust anti-inflammatory effect, decreasing cytokine secretion (including
IL-1β, MCP-1, IL-1α, and IL-6) and preventing immune cell
migration to inflamed lymph nodes in a TNF-α-stimulated murine
model. Our findings highlight CBP/EP300-BRDs as promising targets
for autoimmune therapy, with these non-cytotoxic inhibitors offering
a potential complementary approach for RA and other TNF-α-mediated
inflammatory conditions.