7DCF

Crystal structure of EHMT2 SET domain in complex with compound 10

7DCF の概要

• エントリーDOI: 10.2210/pdb7dcf/pdb
• 分子名称: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• 機能のキーワード: protein-small molecule inhibitor complex, transferase-transferase inhibitor complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67152.84

構造登録者

Suzuki, M.,Katayama, K. (登録日: 2020-10-26, 公開日: 2021-02-10, 最終更新日: 2024-03-27)

主引用文献

Katayama, K.,Ishii, K.,Terashima, H.,Tsuda, E.,Suzuki, M.,Yotsumoto, K.,Hiramoto, K.,Yasumatsu, I.,Torihata, M.,Ishiyama, T.,Muto, T.,Katagiri, T.
Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating beta-Thalassemia and Sickle Cell Disease.
Acs Med.Chem.Lett., 12:121-128, 2021

PubMed Abstract: Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.

PubMed: 33488973
DOI: 10.1021/acsmedchemlett.0c00572

実験手法

X-RAY DIFFRACTION (1.8 Å)