Novel brd4 inhibitors with a unique scaffold exhibit antitumor effects

Abstract

Since bromodomain containing 4 (brd4) has been considered as a prominent cancer target, numerous attempts have been made to develop potent brd4 bromodomain inhibitors. The present study provided a novel chemical scaffold which inhibited brd4 activity. Mid-throughput screening against brd4 bromodomain was performed using alpha-screen and homogeneous time-resolved fluorescence assays. Furthermore, cell cytotoxicity and xenograft assays were performed to examine if the compound was effective both in vitro and in vivo . As a result, it was revealed that compounds having naphthalene-1,4-dione scaffold inhibited the binding of bromodomain to acetylated histone. The compounds with naphthalene-1,4-dione had cytotoxic effects against the Ty82 cell line, a NUT midline carcinoma cell line, whose proliferation is dependent on brd4 activity. A10, one of the compounds with naphthalene-1,4-dione scaffold, also exhibited tumor growth inhibition effects in the xenograft assay. In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo .

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers

“…Recently, Zhou et al [ 75 ] noted that JQ-1 suppressed proliferation, migration and invasion of GC cells via targeting RUNX2/NID1 axis, while BET inhibitor AZD5153 inhibited GC metastasis by regulating Mus81 at both RNA and protein levels[ 76 ]. Kim et al [ 77 ] revealed new BRD4 inhibitor that showed efficiency in I-BET762 resistant GC cell lines[ 77 ]. Additionally, through blocking the expression of c-MYC and YAP1, JQ-1 reduced gastric adenocarcinoma cell growth induced by Gal-3, and the anti-cancer activity could be improved in combination with YAP inhibitors[ 78 ].…”