The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor

The
profound efficacy, yet associated toxicity of pan-BET inhibitors
is well documented. The possibility of an ameliorated safety profile
driven by significantly selective (>100-fold) inhibition of a subset
of the eight bromodomains is enticing, but challenging given the close
homology. Herein, we describe the X-ray crystal structure-directed
optimization of a novel weak fragment ligand with a pan-second bromodomain
(BD2) bias, to potent and highly BD2 selective inhibitors. A template
hopping approach, enabled by our parallel research into an orthogonal
template (15, GSK046), was the basis for the high selectivity
observed. This culminated in two tool molecules, 20 (GSK620)
and 56 (GSK549), which showed an anti-inflammatory phenotype
in human whole blood, confirming their cellular target engagement.
Excellent broad selectivity, developability, and in vivo oral pharmacokinetics
characterize these tools, which we hope will be of broad utility to
the field of epigenetics research.