A preclinical study set to be presented at the ACR Convergence 2024 conference explored the potential of p300 KAT inhibitors to modulate chronic inflammation by targeting proinflammatory transcription across multiple cell types such as TNFα, IL-23, and IL-17A. This approach is designed to downregulate key cytokines involved in autoimmune and inflammatory diseases.

Multiple inflammatory diseases exhibit aberrant proinflammatory transcription, and the researchers noted how biologics targetted at single factors show clinical efficacy, but still do not address the fact that inflammatory disease is multifaceted and multicellular. With this in mind, the researchers looked for a broadly affective small molecule capable of selectively inhibiting proinflammatory transcription to address a root cause of inflammation in multiple cell types.”

They found that p300 KAT inhibition suppresses transcriptional activation of proinflammatory genes through epigenetic modulation, which could address multiple cell types involved in chronic inflammation. Specifically, p300 KAT inhibition led to decreased production of TNFα, IL-23, IL-17A, and soluble IgG without cytotoxic effects. The inhibition also showed reductions in other inflammatory mediators like IL-6, IFNγ, and IL-22 in ex vivo human immune cell studies. p300 KAT inhibition also significantly reduced joint swelling and inflammation in a rat collagen-induced arthritis model.

These findings suggest p300 KAT inhibitors could offer a novel, multi-targeted therapeutic approach for inflammatory and autoimmune conditions including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and some eye conditions.

The abstract will be presented on November 18, 2024 at the 3 PM abstract session.