2. Academic Validation
  3. 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: [email protected].
  • 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.
PMID: 35413416 DOI: 10.1016/j.bmcl.2022.128726
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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