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6ucs

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Discovery and Structure-Based optimization of potent and selective WDR5 inhibitors containing a dihydroisoquinolinone bicyclic core

Structural highlights

6ucs 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 1.85Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent anti-proliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.

Discovery and Structure-Based Optimization of Potent and Selective WD repeat domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.,Tian J, Teuscher K, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey R, Tansey WP, Stauffer S, Lee T, Fesik SW J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01608. PMID:31858797^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
↑ Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, Wu J, Lill JR, Zha J. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2009 Mar;29(5):1176-88. doi: 10.1128/MCB.01599-08. Epub 2008 Dec, 22. PMID:19103755 doi:10.1128/MCB.01599-08
↑ Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J Biol Chem. 2010 Feb 12;285(7):4268-72. doi: 10.1074/jbc.C109.087981. Epub 2009 , Dec 14. PMID:20018852 doi:10.1074/jbc.C109.087981
↑ Han Z, Guo L, Wang H, Shen Y, Deng XW, Chai J. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol Cell. 2006 Apr 7;22(1):137-44. PMID:16600877 doi:10.1016/j.molcel.2006.03.018
↑ Couture JF, Collazo E, Trievel RC. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 2006 Aug;13(8):698-703. Epub 2006 Jul 9. PMID:16829960 doi:10.1038/nsmb1116
↑ Tian J, Teuscher K, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey R, Tansey WP, Stauffer S, Lee T, Fesik SW. Discovery and Structure-Based Optimization of Potent and Selective WD repeat domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core. J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01608. PMID:31858797 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01608

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ucs"

Categories: Homo sapiens | Large Structures | Zhao B

@@ Line 3: / Line 3: @@
 <StructureSection load='6ucs' size='340' side='right'caption='[[6ucs]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ucs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UCS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UCS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ucs]] 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=6UCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UCS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q41:7-[(2-azanyl-3-methyl-imidazol-1-yl)methyl]-2-[(3,5-dimethoxyphenyl)methyl]-5-(4-fluoranyl-2-methyl-phenyl)-3,4-dihydroisoquinolin-1-one'>Q41</scene></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]] 1.85&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ucs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ucs OCA], [http://pdbe.org/6ucs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ucs RCSB], [http://www.ebi.ac.uk/pdbsum/6ucs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ucs ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q41:7-[(2-azanyl-3-methyl-imidazol-1-yl)methyl]-2-[(3,5-dimethoxyphenyl)methyl]-5-(4-fluoranyl-2-methyl-phenyl)-3,4-dihydroisoquinolin-1-one'>Q41</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=6ucs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ucs OCA], [https://pdbe.org/6ucs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ucs RCSB], [https://www.ebi.ac.uk/pdbsum/6ucs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ucs ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 6ucs" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Zhao, B]]
+[[Category: Zhao B]]
-[[Category: Mixed-lineage leukemia]]
-[[Category: Structure-based design]]
-[[Category: Transcription]]
-[[Category: Wdr5]]

6ucs

From Proteopedia

Current revision

Discovery and Structure-Based optimization of potent and selective WDR5 inhibitors containing a dihydroisoquinolinone bicyclic core

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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