7XUD

Structure of G9a in complex with compound 26a

Summary for 7XUD

• Entry DOI: 10.2210/pdb7xud/pdb
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, CHLORIDE ION, ... (8 entities in total)
• Functional Keywords: histone lysine methyltransferase, inhibitor, protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67682.76

Authors

Niwa, H.,Shirai, F.,Sato, S.,Nishigaya, Y.,Umehara, T. (deposition date: 2022-05-18, release date: 2023-03-29, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.45 Å)