8GZC

Crystal structure of EP300 HAT domain in complex with compound 10

8GZC の概要

• エントリーDOI: 10.2210/pdb8gzc/pdb
• 分子名称: Histone acetyltransferase p300, ZINC ION, (2~{R},4~{R})-4-fluoranyl-1-[1-(4-methoxyphenyl)cyclohexyl]carbonyl-~{N}-(1~{H}-pyrazolo[4,3-b]pyridin-5-yl)pyrrolidine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: epigenetics, sbdd, histone acetyltransferase, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106134.95

構造登録者

Takahashi, M.,Hanzawa, H. (登録日: 2022-09-26, 公開日: 2023-01-11, 最終更新日: 2023-11-29)

主引用文献

Kanada, R.,Kagoshima, Y.,Suzuki, T.,Nakamura, A.,Funami, H.,Watanabe, J.,Asano, M.,Takahashi, M.,Ubukata, O.,Suzuki, K.,Aikawa, T.,Sato, K.,Goto, M.,Setsu, G.,Ito, K.,Kihara, K.,Kuroha, M.,Kohno, T.,Ogiwara, H.,Isoyama, T.,Tominaga, Y.,Higuchi, S.,Naito, H.
Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.
J.Med.Chem., 66:695-715, 2023

PubMed 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 and 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 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

PubMed: 36572866
DOI: 10.1021/acs.jmedchem.2c01641

実験手法

X-RAY DIFFRACTION (2 Å)