Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Abstract

Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control bromodomain-related gene expression in human diseases.

Targeting BET Bromodomains for Cancer Treatment

“…BET inhibitors with different chemical scaffolds have been identified [7,8,83,84]. Examples of the main scaffolds are shown in Figure 3.…”

Targeting Cancer Cells with BET Bromodomain Inhibitors

“…The compounds belong to the diazepine family and are analogs of benzodiazepine, which has been used extensively in the clinic as psychoactive drug (Smith et al 2014). Thereafter, the Bradner laboratory and researchers at Glaxo-Smithkline independently published the highly potent and selective BET bromodomain inhibitors JQ1 (a thienotriazolodiazepine) and iBET (a benzodiazepine), respectively (Filippakopoulos et al 2010; Nicodeme et al 2010).…”

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

“…A list of benzodiazepine BET inhibitors and relevant clinical trials are summarized in Table 1 [ Smith et al 2014]. MS417 shares the same thieno-triazolo-1,4-diazepine scaffold with JQ1.…”