7qjg

EED in complex with PRC2 allosteric inhibitor compound 6

spinqualitylabelsall models 7qjg, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qjg is a 4 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 1.8Å Ligands: CL, EKR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development. Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.,Huang Y, Sendzik M, Zhang J, Gao Z, Sun Y, Wang L, Gu J, Zhao K, Yu Z, Zhang L, Zhang Q, Blanz J, Chen Z, Dubost V, Fang D, Feng L, Fu X, Kiffe M, Li L, Luo F, Luo X, Mi Y, Mistry P, Pearson D, Piaia A, Scheufler C, Terranova R, Weiss A, Zeng J, Zhang H, Zhang J, Zhao M, Dillon MP, Jeay S, Qi W, Moggs J, Pissot-Soldermann C, Li E, Atadja P, Lingel A, Oyang C J Med Chem. 2022 Apr 14;65(7):5317-5333. doi: 10.1021/acs.jmedchem.1c02148. Epub , 2022 Mar 30. PMID:35352560 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Polycomb complex proteins 3D structures

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