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==Discovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists== | ==Discovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists== | ||
<StructureSection load='5lwp' size='340' side='right' caption='[[5lwp]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5lwp' size='340' side='right'caption='[[5lwp]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5lwp]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LWP OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5lwp]] is a 1 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=5LWP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LWP FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=79U:4-[3-[2-CHLORANYL-6-(TRIFLUOROMETHYL)PHENOXY]-5-(DIMETHYLCARBAMOYL)INDAZOL-1-YL]BENZOIC+ACID'>79U</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]] 2.4Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79U:4-[3-[2-CHLORANYL-6-(TRIFLUOROMETHYL)PHENOXY]-5-(DIMETHYLCARBAMOYL)INDAZOL-1-YL]BENZOIC+ACID'>79U</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=5lwp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lwp OCA], [https://pdbe.org/5lwp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lwp RCSB], [https://www.ebi.ac.uk/pdbsum/5lwp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lwp ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 23: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bouix-Peter | [[Category: Homo sapiens]] | ||
[[Category: Chantalat | [[Category: Large Structures]] | ||
[[Category: Christin | [[Category: Bouix-Peter C]] | ||
[[Category: Ciesielski | [[Category: Chantalat L]] | ||
[[Category: Comino | [[Category: Christin O]] | ||
[[Category: Duvert | [[Category: Ciesielski F]] | ||
[[Category: Feret | [[Category: Comino C]] | ||
[[Category: Harris | [[Category: Duvert D]] | ||
[[Category: Hennequin | [[Category: Feret C]] | ||
[[Category: Luzy | [[Category: Harris CS]] | ||
[[Category: Musicki | [[Category: Hennequin LF]] | ||
[[Category: Orfila | [[Category: Luzy A-P]] | ||
[[Category: Ouvry | [[Category: Musicki B]] | ||
[[Category: Parnet | [[Category: Orfila D]] | ||
[[Category: Pascau | [[Category: Ouvry G]] | ||
[[Category: Perrin | [[Category: Parnet V]] | ||
[[Category: Pierre | [[Category: Pascau J]] | ||
[[Category: Raffin | [[Category: Perrin A]] | ||
[[Category: Rival | [[Category: Pierre R]] | ||
[[Category: Taquet | [[Category: Raffin C]] | ||
[[Category: Thoreau | [[Category: Rival Y]] | ||
[[Category: Taquet N]] | |||
[[Category: Thoreau E]] | |||
Latest revision as of 21:53, 18 October 2023
Discovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonistsDiscovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedTargeting the IL17 pathway and more specifically the nuclear receptor RORgamma is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORgamma inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models. Discovery of phenoxyindazoles and phenylthioindazoles as RORgamma inverse agonists.,Ouvry G, Bouix-Peter C, Ciesielski F, Chantalat L, Christin O, Comino C, Duvert D, Feret C, Harris CS, Lamy L, Luzy AP, Musicki B, Orfila D, Pascau J, Parnet V, Perrin A, Pierre R, Polge G, Raffin C, Rival Y, Taquet N, Thoreau E, Hennequin LF Bioorg Med Chem Lett. 2016 Dec 1;26(23):5802-5808. doi:, 10.1016/j.bmcl.2016.10.023. Epub 2016 Oct 12. PMID:27815118[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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