9KLC

G9a in complex with the S-isomer of RK-131902 (racemic compound rac-10a)

これはPDB形式変換不可エントリーです。

9KLC の概要

• エントリーDOI: 10.2210/pdb9klc/pdb
• 分子名称: Histone-lysine N-methyltransferase EHMT2, ZINC ION, SINEFUNGIN, ... (5 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: 67529.16

構造登録者

Niwa, H.,Shirai, F.,Sato, S.,Nishigaya, Y.,Ihara, K.,Shirouzu, M.,Umehara, T. (登録日: 2024-11-14, 公開日: 2025-05-21, 最終更新日: 2025-06-04)

主引用文献

Nishigaya, Y.,Takase, S.,Sumiya, T.,Kikuzato, K.,Hiroyama, T.,Maemoto, Y.,Aoki, K.,Sato, T.,Niwa, H.,Sato, S.,Ihara, K.,Nakata, A.,Matsuoka, S.,Hashimoto, N.,Namie, R.,Honma, T.,Umehara, T.,Shirouzu, M.,Koyama, H.,Nakamura, Y.,Yoshida, M.,Ito, A.,Shirai, F.
Discovery of potent substrate-type lysine methyltransferase G9a inhibitors for the treatment of sickle cell disease.
Eur.J.Med.Chem., 293:117721-117721, 2025

PubMed Abstract: Structurally novel inhibitors of the lysine methyltransferase G9a have attracted considerable interest as potential drug candidates for cancer and genetic diseases. Here, a detailed account of potency optimization from early leads 8 and 9 to compound 16g is presented. Our search for an alternative scaffold for the 4-oxo-4,5,6,7-tetrahydro-1H-indole moiety of compounds 8 and 9 via parallel synthesis led to the identification of the 4-pyridin-4-ylamino phenyl substructure in compound 16g. This substructure was found to bind to the enzyme in a horizontally flipped manner compared with compound 8 in X-ray crystallographic analysis. Compound 16g is a highly potent G9a inhibitor (IC = 0.0020 μM) and structurally distinct from other G9a inhibitors reported in the literature. Importantly, compound 16g exhibited dose-dependent induction of γ-globin mRNA in HUDEP-2, leading to elevated γ-globin protein levels and F cell numbers in CD34 bone marrow (BM)‒derived hematopoietic cells. Kinetic studies using surface plasmon resonance (SPR) analysis suggested that compound 16g interacts with G9a via a unique binding mode, as indicated by the markedly higher dissociation constant (K) compared to those of compounds 8 and 9. Interestingly, X-ray crystallographic studies revealed that the binding motif of compound 16g was quite different from our previous series, including RK-701, and somewhat resembles that of endogenous substrates. Insights obtained in this lead optimization exercise on the association/dissociation constants as well as the binding motifs are expected to help in designing future G9a inhibitors for the treatment of sickle cell disease.

PubMed: 40367677
DOI: 10.1016/j.ejmech.2025.117721

実験手法

X-RAY DIFFRACTION (2.15 Å)