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

Abstract

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.

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

“…Consistent with this finding, repression of ZNF606, a known CpG hypermethylated gene (54), was also a predictive feature and exhibited promoter methylation (Supplemental Figure 3D). We confirmed these findings using I-BET-762, an additional BET inhibitor with clinical activity (55). Similar to JQ1, I-BET-762 showed greater activity in CIMP + cell lines (Supplemental Figure 4, A and B).…”

Modulators of Protein–Protein Interactions

“…Competitive inhibition is reasonably well established, and a number of inhibitors have been identified using conventional drug-discovery and design approaches. Prominent examples include a Nutlin follow-up from Roche (RG7112), 30 Abbott (ABT-199), 31 and GSK (I-BET762), 32 which all entered clinical trials ( Figure 2A−C). Challenges associated with competitive inhibition center on achieving sufficiently potent and selective recognition of either protein surface for inhibition to occur and the concomitant liability that might be introduced in terms of inhibiting all PPIs of the target protein.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…BRD4 also facilitates transcription elongation. Highly selective BET bromodomain inhibitors, such as JQ-1, 127-129 I-BET151, 130,131 I-BET762, 132 INCB054329, 126 and OTX-015, 133 have been generated to specifically target the recognition of acetylated lysine residues of BETs. Competitive binding with a BET bromodomain inhibitor blocks the binding between BRD4 and acetylated histones, leading to transcriptional inactivation (Fig.…”