Discovery of Highly Potent BET Inhibitors based ona Tractable Tricyclic Scaffold

The bromodomain and extra-terminal domain (BET) protein family is a class of epigenetic reader proteins that recognize <i>N</i>-acetylated lysine residues in histone tails, playing a crucial role in gene expression and cell transcription. Selective inhibition of bromodomain-containing proteins (BRDs) disrupts transcription in key oncogenes. Over the past decade there has been considerable interest in developing small molecule BET inhibitors for the treatment of hematological malignancies and solid tumors. Herein, we report the development of a triazinoindole scaffold capable of the inhibition of bromodomain-containing protein 4 (BRD4), with either dimethylisoxazole or dimethyltriazole substituents acting as chemomimetics of the <i>N</i>-acetylated lysine residues. Derivatization of the parent scaffold afforded the lead compound, which displays low nanomolar affinity toward BRD4-BD1 with a favorable physicochemical and <i>in vitro</i> stability profile.