Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening

The bromodomain and
extraterminal (BET) family of bromodomain-containing
proteins are important regulators of the epigenome through their ability
to recognize N-acetyl lysine (KAc) post-translational
modifications on histone tails. These interactions have been implicated
in various disease states and, consequently, disruption of BET–KAc
binding has emerged as an attractive therapeutic strategy with a number
of small molecule inhibitors now under investigation in the clinic.
However, until the utility of these advanced candidates is fully assessed
by these trials, there remains scope for the discovery of inhibitors
from new chemotypes with alternative physicochemical, pharmacokinetic,
and pharmacodynamic profiles. Herein, we describe the discovery of
a candidate-quality dimethylpyridone benzimidazole compound which
originated from the hybridization of a dimethylphenol benzimidazole
series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening.
Optimization via structure- and property-based design led to I-BET469,
which possesses favorable oral pharmacokinetic properties, displays
activity in vivo, and is projected to have a low human efficacious
dose.