Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I‑BET282E, Suitable for Clinical Progression

The
functions of the bromodomain and extra terminal (BET) family
of proteins have been implicated in a wide range of diseases, particularly
in the oncology and immuno-inflammatory areas, and several inhibitors
are under investigation in the clinic. To mitigate the risk of attrition
of these compounds due to structurally related toxicity findings,
additional molecules from distinct chemical series were required.
Here we describe the structure- and property-based optimization of
the in vivo tool molecule I-BET151 toward I-BET282E,
a molecule with properties suitable for progression into clinical
studies.