MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM) with preference for the first bromodomain over the second. MS436 effectively blocks BRD4 transcriptional activity in lipopolysaccharide-induced production of both nitric oxide and IL-6 in mouse macrophages (IC50 values are 3.8 and 4.9 ?M, respectively). MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.
