7BUC

Crystal structure of EHMT2 SET domain in complex with compound 13

Summary for 7BUC

• Entry DOI: 10.2210/pdb7buc/pdb
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: protein-small molecule inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 67208.86

Authors

Suzuki, M.,Mizuno, M.,Katayama, K. (deposition date: 2020-04-06, release date: 2020-11-11, Last modification date: 2024-11-06)

Primary citation

Katayama, K.,Ishii, K.,Tsuda, E.,Yotsumoto, K.,Hiramoto, K.,Suzuki, M.,Yasumatsu, I.,Igarashi, W.,Torihata, M.,Ishiyama, T.,Katagiri, T.
Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines.
Bioorg.Med.Chem.Lett., 30:127475-127475, 2020

PubMed Abstract: The discovery and optimization of a novel series of G9a/GLP (EHMT2/1) inhibitors are described. Starting from known G9a/GLP inhibitor 5, efforts to explore the structure-activity relationship and optimize drug properties led to a novel compound 13, the side chain of which was converted to tetrahydroazepine. Compound 13 showed increased G9a/GLP inhibitory activity compared with compound 5. In addition, compound 13 exhibited improved human ether-a-go-go related gene (hERG) inhibitory activity over compound 5 and also improved pharmacokinetic profile in mice (oral bioavailability: 17 to 40%). Finally, the co-crystal structure of G9a in complex with compound 13 provides the basis for the further development of tetrahydroazepine-based G9a/GLP inhibitors.

PubMed: 32781218
DOI: 10.1016/j.bmcl.2020.127475

Experimental method

X-RAY DIFFRACTION (2.6 Å)