The bromodomain and extra-terminal domain (BET) family of bromodomain-containing proteins (BCPs) are important regulators of the epigenome through their ability to recognise acetylated lysine post-translational modifications on histone tails. These interactions have been implicated in a variety of disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with several 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. Accordingly, this poster describes the development of the potent benzimidazole dimethylpyridinone BET inhibitor 2 (Figure 1) which exhibits favorable pharmacokinetic properties and a low predicted human efficacious dose. This compound originated from Encoded Library Technology (ELT) hit dimethylphenol benzimidazole 1 (Figure 1), which was modified to an improved dimethylpyridinone benzimidazole series using structure-based design. Subsequent optimisation of activity, BCP selectivity and pharmacokinetic properties was carried out leading to benzimidazole dimethylpyridinone 2.

Discovery of a bromodomain and extraterminal (BET) inhibitor with a low predicted human dose derived from an encoded library technology hit

2019 Fall National Meeting

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