View source for 7qk4


==EED in complex with PRC2 allosteric inhibitor compound 22 (MAK683)==
<StructureSection load='7qk4' size='340' side='right'caption='[[7qk4]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qk4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QK4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QK4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.602&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EJR:N-[(5-fluoranyl-2,3-dihydro-1-benzofuran-4-yl)methyl]-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine'>EJR</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7qk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qk4 OCA], [https://pdbe.org/7qk4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qk4 RCSB], [https://www.ebi.ac.uk/pdbsum/7qk4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qk4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/EED_HUMAN EED_HUMAN] Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.<ref>PMID:9584199</ref> <ref>PMID:10581039</ref> <ref>PMID:14532106</ref> <ref>PMID:15385962</ref> <ref>PMID:15231737</ref> <ref>PMID:15225548</ref> <ref>PMID:16357870</ref> <ref>PMID:18285464</ref> <ref>PMID:20974918</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:35352560</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qk4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Luo X]]
[[Category: Scheufler C]]
[[Category: Zhang H]]
[[Category: Zhao K]]
[[Category: Zhao M]]