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

26 March 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.