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
  • 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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