Discovery of Epigenetic Regulator I‑BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure–activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers

Discovery and Optimization of Potent, Selective, and <i>in Vivo</i> Efficacious 2‑Aryl Benzimidazole BCATm Inhibitors

To identify BCATm inhibitors suitable for <i>in vivo</i> study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)­cyclohexyl)-<i>N</i>-methyl-2-(pyridin-2-yl)-1<i>H</i>-benzo­[d]­imidazole-5-carboxamide (<b>8b</b>) with much improved PK properties. X-ray structure revealed that <b>8b</b> binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, <b>8b</b> raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition