Development of a novel class of CBP/EP300 bromodomain inhibitors which block TNF-α induced NFκB signaling

Tumor Necrosis Factor α (TNF-α) is an inflammatory cytokine that is a key mediator in autoimmune disorders such as Crohn’s disease and rheumatoid arthritis (RA). Targeting epigenetic regulators of cytokine transcription and signaling is a promising therapeutic approach. However, the specific mechanisms by which they contribute to the immune response are not well established yet. Here, we present a new class of selective CBP/EP300-bromodomain (BRD) inhibitors comprising a 3-methylcinnoline as acetyl-lysine mimic discovered by high-throughput docking of a fragment library. These compounds inhibit NFκB signaling in THP-1 cells, reducing TNF-α-induced cytokine expression in vitro. Furthermore, when tested in vivo, BRD inhibitors reduced the pro-inflammatory response by decreasing the secretion of IL-1β, MCP-1, IL-1α, and IL-6 from TNF-α-stimulated animals and inhibiting the migration of innate immune cells towards the draining lymph node. The results of this study confirmed CBP/EP300-BRD as valid therapeutic targets for autoimmune diseases and our inhibitors represent a promising new class of non-cytotoxic therapeutic agents for treating RA.