7xud

Structure of G9a in complex with compound 26a

spinqualitylabelsall models 7xud, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7xud is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.45Å Ligands: CL, EDO, I6Z, SFG, TRS, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 rac-10a 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 in vitro characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of 26j (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC(50) = 27/53 nM). Compound 26j exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells in vitro. Moreover, compound 26j showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) in vivo mouse model without overt acute toxicity. Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.,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 J Med Chem. 2023 Mar 23;66(6):4059-4085. doi: 10.1021/acs.jmedchem.2c02059. Epub , 2023 Mar 7. PMID:36882960 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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