I-BET-762

I-BET-762 (GSK525762) is a small molecule inhibitor of the BET (Bromodomain and Extra-Terminal) family of bromodomain-containing proteins. BET inhibitor I-BET-762 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. I-BET-762 (GSK525762) was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Treatment of naive CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells.