7msb
From Proteopedia
(Difference between revisions)
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==Structure of EED bound to EEDi-4259== | ==Structure of EED bound to EEDi-4259== | ||
| - | <StructureSection load='7msb' size='340' side='right'caption='[[7msb]]' scene=''> | + | <StructureSection load='7msb' size='340' side='right'caption='[[7msb]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MSB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MSB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7msb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MSB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MSB FirstGlance]. <br> |
| - | </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=7msb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7msb OCA], [https://pdbe.org/7msb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7msb RCSB], [https://www.ebi.ac.uk/pdbsum/7msb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7msb ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZNG:(9aM,12aS)-12-{[(5-fluoro-1-benzofuran-4-yl)methyl]amino}-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one'>ZNG</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=7msb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7msb OCA], [https://pdbe.org/7msb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7msb RCSB], [https://www.ebi.ac.uk/pdbsum/7msb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7msb ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases. | ||
| + | |||
| + | Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression.,Rej RK, Wang C, Lu J, Wang M, Petrunak E, Zawacki KP, McEachern D, Yang CY, Wang L, Li R, Chinnaswamy K, Wen B, Sun D, Stuckey JA, Zhou Y, Chen J, Tang G, Wang S J Med Chem. 2021 Oct 14;64(19):14540-14556. doi: 10.1021/acs.jmedchem.1c01059., Epub 2021 Oct 6. PMID:34613724<ref>PMID:34613724</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7msb" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Petrunak E]] | + | [[Category: Petrunak, E]] |
| - | [[Category: Stuckey J]] | + | [[Category: Stuckey, J]] |
| + | [[Category: Gene regulation-inhibitor complex]] | ||
| + | [[Category: Polycomb repressive complex 2]] | ||
Revision as of 15:52, 27 October 2021
Structure of EED bound to EEDi-4259
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