Background/Purpose: Across inflammatory and autoimmune diseases, pathologic signaling converges in the nucleus to elevate transcription of numerous inflammatory effectors such as cytokines, chemokines and antibodies. Biologics targeting single factors including TNFα, IL-23 and IL-17A have demonstrated clinical efficacy but fail to account for the multifaceted and multicellular nature of inflammatory disease. We reasoned that an oral small molecule able to selectively inhibit proinflammatory transcription could address a root cause of inflammation in multiple cell types and have broad clinical utility. Through analysis of transcriptional regulatory networks (TRNs) of immune cell types, we found that inhibition of the lysine acetyltransferase (KAT) domain of p300, a critical cofactor of proinflammatory transcription factors, results in selective downregulation of pathogenic cytokines such as TNFα, IL-23, IL-17A as well as antibodies. Here we developed a series of p300 KAT inhibitors for use in inflammatory diseases and investigated their ability to selectively modulate proinflammatory transcription ex vivo and in vivo.

Methods: We mapped TRNs of immune cell types using chromatin and gene expression data to identify key proinflammatory genes regulated by p300 at the transcriptional level. Ex vivo immune cell functional assays in primary cells were used to examine the effects of p300 KAT inhibition. The IL-17A-dependent collagen induced arthritis (CIA) model was used to study inflammation in rats. 

Results: Inflammatory stimuli result in hyperacetylation of chromatin selectively at the loci of key effector genes. In ex vivo primary cell models, p300 KAT inhibition interdicts this proinflammatory signaling and blunts the production of multiple clinically validated molecules including TNFα, IL-23, IL-17A and soluble IgG at non-cytotoxic concentrations. Changes to chromatin and transcription are highly selective and occur at doses corresponding to partial inhibition of p300 KAT activity. p300 KAT inhibition also led to significantly decreased inflammation in the rat CIA model, as measured by joint swelling, clinical score and histopathology. 

Conclusion: Aberrant proinflammatory transcription is a hallmark of multiple inflammatory diseases. By selectively inhibiting proinflammatory transcription, p300 KAT inhibition can modulate the activity and function of multiple pro-inflammatory signaling pathways driving chronic inflammatory diseases at well tolerated in vivo exposures. These data suggest potential benefit across inflammatory disease indications and motivate our development of a clinical p300 KAT inhibitor as an anti-inflammatory therapeutic.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/p300-kat-inhibition-selectively-targets-multiple-cell-types-involved-in-chronic-inflammation-and-downregulates-key-inflammatory-cytokines/