Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring

[Display omitted] EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly sel...

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Published in:Bioorganic & medicinal chemistry letters 2022-06, Vol.66, p.128726-128726, Article 128726
Main Authors: Kanada, Ryutaro, Kagoshima, Yoshiko, Asano, Masayoshi, Suzuki, Takashi, Murata, Takeshi, Haruta, Makoto, Takahashi, Mizuki, Ubukata, Osamu, Hashimoto, Kazuyuki, Obata, Kenichi, Kihara, Kawori, Kuroha, Mutsumi, Banjo, Toshihiro, Togashi, Noriko, Sato, Kazumi, Yamamoto, Yuka, Suzuki, Kanae, Isoyama, Takeshi, Tominaga, Yuichi, Higuchi, Saito, Naito, Hiroyuki
Format: Article
Language:English
Subjects:
Animals
Drug discovery
EP300/CBP selective inhibitor
Histone acetyltransferase
Histone Acetyltransferases
Mice
Scaffold hopping
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Summary:[Display omitted] EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128726