8GZC

Crystal structure of EP300 HAT domain in complex with compound 10

Summary for 8GZC

• Entry DOI: 10.2210/pdb8gzc/pdb
• Descriptor: 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)
• Functional Keywords: epigenetics, sbdd, histone acetyltransferase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 106134.95

Authors

Takahashi, M.,Hanzawa, H. (deposition date: 2022-09-26, release date: 2023-01-11, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)