Proinflammatory stimuli induce rapid transcriptional responses. They are essential for host defense from infection. An inflammatory response involves a variety of cell types and expression of inflammatory mediators such as cytokines and chemokines. Cytokines, including interleukin-6 (IL-6) and interleukin-1β (IL-1β), have potent pro-inflammatory actions. Epigenetics regulate gene expression. Histone acetylation is one such modification associated with active gene transcription. Acetylation occurs on lysine residues. The chromatin readers such as the bromodomain and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4, and the testis-specific BRDT) can recognize them. In addition, BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET bromodomain inhibitors (BETi) have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Here, RVX-297, an orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo.

RVX-297, a potent, orally bioavailable BET bromodomain inhibitor with selectivity for BD2, is effective in acute inflammation and autoimmunity models.

RVX-297 shows IC₅₀s of 0.08, 0.05, and 0.02 μM for BRD2(BD2), BRD3(BD2), and BRD4(BD2), respectively. It decreases proinflammatory gene expression in synovial fibroblasts. It also displaces BET proteins from the promoters of sensitive genes and disrupted the recruitment of active RNA polymerase II. In addition, it reduces the gene expression of inflammatory mediators in vitro. RVX-297 suppresses IL-6 gene induction in human U937 macrophages, mouse primary B cells isolated from the spleen, mouse BMDMs, and THP-1 monocytes in a dose-dependent manner. Furthermore, it represses IL-1β expression in LPS-stimulated mouse BMDMs, with an IC₅₀ of 0.4-3 μM. RVX-297 inhibits MCP-1 expression in unstimulated human PBMCs with an IC₅₀ of 0.4 μM. In addition, it inhibits antigen stimulation of T cells and the induction of IL-17 expression.

RVX-297 inhibits the progression of pathology in the rat collagen-induced arthritis model. RVX-297 inhibits the progression of pathology in the mouse collagen-induced arthritis model. It also suppresses cytokine production in LPS-treated mice.

In summary, RVX-297, a BET bromodomain inhibitor, maintains anti-inflammatory properties and is effective in models of acute inflammation and autoimmunity.

Reference:

Jahagirdar R, et al. Mol Pharmacol. 2017;92(6):694-706.