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

Ryutaro Kanada,Yoshiko Kagoshima,Masayoshi Asano,Takashi Suzuki,Takeshi Murata, Makoto Haruta,Mizuki Takahashi,Osamu Ubukata,Kazuyuki Hashimoto, Kenichi Obata,Kawori Kihara,Mutsumi Kuroha,Toshihiro Banjo,Noriko Togashi,Kazumi Sato,Yuka Yamamoto,Kanae Suzuki,Takeshi Isoyama,Yuichi Tominaga,Saito Higuchi,Hiroyuki Naito

Bioorganic & Medicinal Chemistry Letters（2022）

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摘要

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.

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关键词

Drug discovery,Histone acetyltransferase,EP300/CBP selective inhibitor,Scaffold hopping

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