Description
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.
Uses
MS 436 is a potent bromodomain inhibitor, binding to BRD4 and more tightly to subdomain BD1 than BD2. These domains play a key role in inflammatory gene expression, mitosis and viral/host interaction. Applications involving innhibition of bromodomains include decrease in cell proliferation for leukemia and destruction of tumor cells.
Biological Activity
ms436 is a potent and selective small-molecule inhibitor of brd4 with ki values of ＜0.085μm and 0.34μm, respectively for brd1 and brd2 [1].brd4 plays a role in gene transcription and is a drug target for cancer and inflammation. it has two bromodomains. ms436 is a diazobenzene compound, it is designed from the sar studies to have higher selectivity. in vitro fluorescent anisotropy assay shows ms436 has about 10-fold higher affinity of brd1 over brd2. ms436 binds to brd4 through a set of water-mediated interaction and this is the molecular basis for the binding affinity. ms436 also has activity to cbp brd. in raw264.7 cells, ms436 can block nf-κb-directed no production and block the expression of proinflammatory cytokine interleukin (il)-6 induced by lps [1].
References
[1] zhang g, plotnikov an, rusinova e, shen t, morohashi k, joshua j, zeng l, mujtaba s, ohlmeyer m, zhou mm. structure-guided design of potent diazobenzene inhibitors for the bet bromodomains. j med chem. 2013 nov 27;56(22):9251-64.
