Novel brd4 inhibitors with a unique scaffold exhibit antitumor effects

Kim,Young Hun; Kim,Minsung; Kim,Ji Eun; Yoo,Miyoun; Lee,Heung Kyoung; Lee,Chong Ock; Yoo,Minjin; Jung,Kwan-Young; Kim,Yeongrin; Choi,Sang Un; Park,Chi Hoon

doi:10.3892/ol.2021.12734

Novel brd4 inhibitors with a unique scaffold exhibit antitumor effects

Authors:
- Young Hun Kim
- Minsung Kim
- Ji Eun Kim
- Miyoun Yoo
- Heung Kyoung Lee
- Chong Ock Lee
- Minjin Yoo
- Kwan-Young Jung
- Yeongrin Kim
- Sang Un Choi
- Chi Hoon Park
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Affiliations: Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Published online on: April 14, 2021 https://doi.org/10.3892/ol.2021.12734
Article Number: 473
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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