2. Academic Validation
  3. Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor

  • J Med Chem. 2023 Jan 12;66(1):695-715. doi: 10.1021/acs.jmedchem.2c01641.
Ryutaro Kanada 1,  Yoshiko Kagoshima 1,  Takashi Suzuki 1,  Akifumi Nakamura 1,  Hideaki Funami 1,  Jun Watanabe 1,  Masayoshi Asano 1,  Mizuki Takahashi 2,  Osamu Ubukata 2,  Kanae Suzuki 1,  Tomoya Aikawa 1,  Kazumi Sato 2,  Megumi Goto 1,  Genzui Setsu 1,  Kentaro Ito 1,  Kawori Kihara 2,  Mutsumi Kuroha 2,  Takashi Kohno 3,  Hideaki Ogiwara 4,  Takeshi Isoyama 1,  Yuichi Tominaga 1,  Saito Higuchi 1,  Hiroyuki Naito 1
Affiliations

Affiliations

  • 1 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo140-8710, Japan.
  • 2 Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo134-8630, Japan.
  • 3 Division of Genome Biology, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo104-0045, Japan.
  • 4 Division of Cancer Therapeutics, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo104-0045, Japan.
PMID: 36572866 DOI: 10.1021/acs.jmedchem.2c01641
Abstract

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for Cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

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