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

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

  • Bioorg Med Chem Lett. 2022 Jun 15;66:128726. doi: 10.1016/j.bmcl.2022.128726.
Ryutaro Kanada 1 Yoshiko Kagoshima 2 Masayoshi Asano 2 Takashi Suzuki 2 Takeshi Murata 2 Makoto Haruta 3 Mizuki Takahashi 3 Osamu Ubukata 3 Kazuyuki Hashimoto 2 Kenichi Obata 3 Kawori Kihara 3 Mutsumi Kuroha 3 Toshihiro Banjo 2 Noriko Togashi 2 Kazumi Sato 3 Yuka Yamamoto 3 Kanae Suzuki 2 Takeshi Isoyama 2 Yuichi Tominaga 2 Saito Higuchi 2 Hiroyuki Naito 2
Affiliations

Affiliations

  • 1 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: kanada.ryutaro.nw@daiichisankyo.co.jp.
  • 2 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
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.

Keywords

Drug discovery; EP300/CBP selective inhibitor; Histone acetyltransferase; Scaffold hopping.

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