RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Abstract

Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.

Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases

“…Recent studies focused on the oral administration of BET inhibitors 36 37 85 or the use of BRD2-selective inhibitors such as RVX-297. 37 The good druggability of BRD will likely lead to the continuing development of inhibitors that will further boost the research in this field.…”

“… 60 67 Recently, the use of a BDR2 specific and orally active BET inhibitor, RVX-297, was shown to be efficient in decreasing the arthritis scores in CIA mice and rats, as well as in mice with collagen antibody-induced arthritis. 37 The beneficial effects of BET inhibitors in arthritis models in vivo were mainly attributed to the suppressive effects on Th17 cell differentiation and the reduced expression of Th17-associated cytokines, including IL17, IL21 and granulocyte macrophage-colony stimulating factor. 34 37 The aberrant generation and activation of Th17 cells, a subset of T helper cells, is one of the key mechanisms leading to autoimmune conditions.…”

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

“…Brd2 and Brd4 physically associate with the promoters of inflammatory cytokine genes, reducing production of cytokines TNFα, IL-6, MCP-1 in vitro and in vivo. Also, one study on the transgenic model of AD (3×Tg mice) confirmed the important function of BET proteins in regulating brain gene expression in neuro-inflammation-related conditions, including AD [80]. Importantly, Brd3 gene is Ca 2+ -responsive gene [81].…”

“…A growing body of evidence indicates that epigenetic control mechanisms are involved in regulating the immune system. Recent studies confirmed that BET proteins may affect the progression of inflammation and demonstrated that they are critical for macrophage activation [35,[77][78][79][80]. Brd2 and Brd4 physically associate with the promoters of inflammatory cytokine genes, reducing production of cytokines TNFα, IL-6, MCP-1 in vitro and in vivo.…”

Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice

“…It is interesting that BET proteins are critical for inflammatory response and Brd2 is essential for pro-inflammatory cytokine production [59]. Emerging preclinical and clinical evidence show a number of small molecule BET inhibitors with a potent anti-inflammatory activity [60,61]. Thus, the reduced inflammation observed in HET kidneys could be due to Brd2's up-regulation of cytoprotective genes when it is haplodeficient, but it could also be due to a down-regulation of pro-inflammatory genes.…”