Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit

Second-generation bromodomain and
extra terminal (BET) inhibitors,
which selectively target one of the two bromodomains in the BET proteins,
have begun to emerge in the literature. These inhibitors aim to help
determine the roles and functions of each domain and assess whether
they can demonstrate an improved safety profile in clinical settings
compared to pan-BET inhibitors. Herein, we describe the discovery
of a novel BET BD2-selective chemotype using a structure-based drug
design from a hit identified by DNA-encoded library technologies,
showing a structural differentiation from key previously reported
greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and
ABBV-744. Following a structure-based hypothesis for the selectivity
and optimization of the physicochemical properties of the series,
we identified 60 (GSK040), an in vitro ready and in vivo
capable BET BD2-inhibitor of unprecedented selectivity (5000-fold)
against BET BD1, excellent selectivity against other bromodomains,
and good physicochemical properties. This novel chemical probe can
be added to the toolbox used in the advancement of epigenetics research.