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

Year: 2025

Type: article

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.

Source: Zurich Open Repository and Archive (University of Zurich)

DOI: 10.5167/uzh-278795

Authors: Gosselé, Katherine A, Latino, Irene, Laul, Eleen, Kirillova, Mariia S, Pascanu, Vlad, Carloni, Emanuele, Bedi, Rajiv K, Pizzichetti, Chiara, Caflisch, Amedeo, González, Santiago F, Nevado, Cristina

Language: English

Topic: Protein Degradation and Inhibitors

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W6892282069

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