7XUA

Structure of G9a in complex with compound 10a

7XUA の概要

• エントリーDOI: 10.2210/pdb7xua/pdb
• 分子名称: Histone-lysine N-methyltransferase EHMT2, ZINC ION, SINEFUNGIN, ... (7 entities in total)
• 機能のキーワード: histone lysine methyltransferase, inhibitor, protein-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: 67591.29

構造登録者

Niwa, H.,Shirai, F.,Sato, S.,Nishigaya, Y.,Umehara, T. (登録日: 2022-05-18, 公開日: 2023-03-29, 最終更新日: 2023-11-29)

主引用文献

Nishigaya, Y.,Takase, S.,Sumiya, T.,Kikuzato, K.,Sato, T.,Niwa, H.,Sato, S.,Nakata, A.,Sonoda, T.,Hashimoto, N.,Namie, R.,Honma, T.,Umehara, T.,Shirouzu, M.,Koyama, H.,Yoshida, M.,Ito, A.,Shirai, F.
Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.
J.Med.Chem., 66:4059-4085, 2023

PubMed Abstract: Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit - obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC = 27/53 nM). Compound exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells . Moreover, compound showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) mouse model without overt acute toxicity.

PubMed: 36882960
DOI: 10.1021/acs.jmedchem.2c02059

実験手法

X-RAY DIFFRACTION (1.87 Å)