Abstract
Bromodomain and extra-terminal (BET) domain proteins are chromatin adapters that bind acetylated histone marks via two tandem bromodomains (BD1 and BD2) to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET bromodomain inhibitors (BETi) that are non-selective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. While both BD1 and BD2 bind acetylated histone residues, they may independently regulate 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-BETi that non-selectively bind BET bromodomains. In the lipopolysaccharide (LPS) model of inflammation, RVX-297 reduced pro-inflammatory 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 (rCIA and mCIA) and mouse collagen antibody induced arthritis (mCAIA). Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (EAE; 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.
- The American Society for Pharmacology and Experimental Therapeutics