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

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

doi:10.1016/j.bmcl.2022.128726

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

Ryutaro Kanada, Yuka Yamamoto + Show 19 more

https://doi.org/10.1016/j.bmcl.2022.128726

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Journal: Bioorganic & Medicinal Chemistry Letters	Publication Date: Apr 9, 2022
Citations: 2

Affiliation: Daiichi-Sankyo (Japan)

#SRY-box Transcription Factor 2 #Human Lung Squamous Carcinoma Cell + Show 8 more

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Abstract

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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