BiBET

It is interesting to note the targeting approach of engaging two bromodomains simultaneously using a synthetic agent with a bivalent binding mode.

This is an extremely potent (picomolar) inhibitor of BRD4. Biophysical evidence suggests this pseudosymmetric molecule binds bivalently to the tandem BD1/2 domains (at nonsaturating ligand concentrations), which might explain its unusually high affinity towards BRD4. This mode of binding may provide additional selectivity at lower concentrations towards BET proteins with tandem BD domains. Unfortunately, as with other BRD inhibitors, this molecule may not be selective for BRD4 within the family of BRD proteins, and cellular data suggests that it might in fact engage BRD2/3/T with similar potency to BRD4. At higher concentrations (>1 uM), additional BD containing proteins and some kinases might be inhibited. As such, a low concentration (low nanomolar) may be recommended for cell-based assays.

This is a highly potent (10 nM in cells) BET-family inhibitor.