7uas
From Proteopedia
(Difference between revisions)
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==Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization== | ==Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization== | ||
| - | <StructureSection load='7uas' size='340' side='right'caption='[[7uas]]' scene=''> | + | <StructureSection load='7uas' size='340' side='right'caption='[[7uas]], [[Resolution|resolution]] 1.81Å' 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=7UAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UAS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7uas]] 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=7UAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UAS 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=7uas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uas OCA], [https://pdbe.org/7uas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uas RCSB], [https://www.ebi.ac.uk/pdbsum/7uas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uas ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.808Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MBU:(5P)-2-[(S)-cyclopropyl(4-methylpyridin-2-yl)methyl]-5-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-[(2-methyl-1H-imidazol-1-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one'>MBU</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=7uas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uas OCA], [https://pdbe.org/7uas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uas RCSB], [https://www.ebi.ac.uk/pdbsum/7uas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uas ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new in vivo lead series. Importantly, this new series of compounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueous solubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition. | ||
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| + | Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.,Teuscher KB, Meyers KM, Wei Q, Mills JJ, Tian J, Alvarado J, Sai J, Van Meveren M, South TM, Rietz TA, Zhao B, Moore WJ, Stott GM, Tansey WP, Lee T, Fesik SW J Med Chem. 2022 Apr 18. doi: 10.1021/acs.jmedchem.2c00195. PMID:35436124<ref>PMID:35436124</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7uas" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Zhao B]] | [[Category: Zhao B]] | ||
Current revision
Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization
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