8aqn
From Proteopedia
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| - | ==Crystal structure of PPARG and | + | ==Crystal structure of PPARG and NCOR2 with BAY-4931, an inverse agonist (compound 6c)== |
<StructureSection load='8aqn' size='340' side='right'caption='[[8aqn]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='8aqn' size='340' side='right'caption='[[8aqn]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8aqn]] is a 4 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=8AQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AQN FirstGlance]. <br> | <table><tr><td colspan='2'>[[8aqn]] is a 4 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=8AQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AQN FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O0U:2-chloranyl-~{N}-[2-(4-ethylphenyl)-1,3-benzoxazol-5-yl]-5-nitro-benzamide'>O0U</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]] 1.9Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O0U:2-chloranyl-~{N}-[2-(4-ethylphenyl)-1,3-benzoxazol-5-yl]-5-nitro-benzamide'>O0U</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=8aqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqn OCA], [https://pdbe.org/8aqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqn RCSB], [https://www.ebi.ac.uk/pdbsum/8aqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqn ProSAT]</span></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=8aqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqn OCA], [https://pdbe.org/8aqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqn RCSB], [https://www.ebi.ac.uk/pdbsum/8aqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqn ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-gamma (PPARG or PPARgamma) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARgamma is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARgamma that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARgamma target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARgamma inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARgamma inverse-agonism. | The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-gamma (PPARG or PPARgamma) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARgamma is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARgamma that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARgamma target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARgamma inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARgamma inverse-agonism. | ||
| - | Discovery and Structure-Based Design of Potent Covalent PPARgamma Inverse-Agonists BAY-4931 and BAY-0069.,Orsi DL, Pook E, Brauer N, Friberg A, Lienau P, Lemke CT, Stellfeld T, Bruggemeier U, Putter V, Meyer H, Baco M, Tang S, Cherniack AD, Westlake L, Bender SA, Kocak M, Strathdee CA, Meyerson M, Eis K, Goldstein JT J Med Chem. 2022 | + | Discovery and Structure-Based Design of Potent Covalent PPARgamma Inverse-Agonists BAY-4931 and BAY-0069.,Orsi DL, Pook E, Brauer N, Friberg A, Lienau P, Lemke CT, Stellfeld T, Bruggemeier U, Putter V, Meyer H, Baco M, Tang S, Cherniack AD, Westlake L, Bender SA, Kocak M, Strathdee CA, Meyerson M, Eis K, Goldstein JT J Med Chem. 2022 Nov 10;65(21):14843-14863. doi: 10.1021/acs.jmedchem.2c01379. , Epub 2022 Oct 21. PMID:36270630<ref>PMID:36270630</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8aqn" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8aqn" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of PPARG and NCOR2 with BAY-4931, an inverse agonist (compound 6c)
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Categories: Homo sapiens | Large Structures | Braeuer N | Friberg A | Goldstein J | Lemke CT | Orsi DL | Pook E | Puetter V | Stellfeld T
