# Discovery of Highly Potent BET Inhibitors based on a Tractable Tricyclic Scaffold

## TL;DR

This paper introduces a new class of potent BET inhibitors based on a tricyclic scaffold that effectively targets BRD4, a protein involved in gene regulation and cancer.

## Contribution

The novel contribution is the development of a triazinoindole scaffold with chemomimetic substituents that inhibit BRD4 with high potency.

## Key findings

- The triazinoindole scaffold effectively inhibits BRD4 with low nanomolar affinity.
- The lead compound has favorable physicochemical and in vitro stability properties.
- Dimethylisoxazole and dimethyltriazole substituents mimic N-acetylated lysine residues in histone tails.

## Abstract

The bromodomain and
extra-terminal domain (BET) protein family
is a class of epigenetic reader proteins that recognize N-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 N-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 in vitro stability
profile.