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6ivx

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Revision as of 12:44, 13 March 2019

Discovery of the Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.

Structural highlights

6ivx is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	RORG (HUMAN), NCOR2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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. [NCOR2_HUMAN] Transcriptional corepressor of NR4A2/NURR1 and acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state (By similarity). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 5 have different affinities for different nuclear receptors.

Publication Abstract from PubMed

Starting from a previously reported RORgamma inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORgamma inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

Discovery of Second Generation RORgamma Inhibitors Composed of an Azole Scaffold.,Kotoku M, Maeba T, Fujioka S, Yokota M, Seki N, Ito K, Suwa Y, Ikenogami T, Hirata K, Hase Y, Katsuda Y, Miyagawa N, Arita K, Asahina K, Noguchi M, Nomura A, Doi S, Adachi T, Crowe P, Tao H, Thacher S, Hashimoto H, Suzuki T, Shiozaki M J Med Chem. 2019 Mar 1. doi: 10.1021/acs.jmedchem.8b01567. PMID:30776227^[1]

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

References

↑ Kotoku M, Maeba T, Fujioka S, Yokota M, Seki N, Ito K, Suwa Y, Ikenogami T, Hirata K, Hase Y, Katsuda Y, Miyagawa N, Arita K, Asahina K, Noguchi M, Nomura A, Doi S, Adachi T, Crowe P, Tao H, Thacher S, Hashimoto H, Suzuki T, Shiozaki M. Discovery of Second Generation RORgamma Inhibitors Composed of an Azole Scaffold. J Med Chem. 2019 Mar 1. doi: 10.1021/acs.jmedchem.8b01567. PMID:30776227 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01567

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Discovery of the Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.==
-<StructureSection load='6ivx' size='340' side='right'  caption='[[6ivx]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
+<StructureSection load='6ivx' size='340' side='right'caption='[[6ivx]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ivx]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IVX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IVX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ivx]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IVX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IVX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AYO:(4S)-4-[4-cyclopropyl-5-(2,2-dimethylpropyl)[3,5-bi-1,2-oxazol]-3-yl]-6-[(2,4-dichlorophenyl)amino]-6-oxohexanoic+acid'>AYO</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NCOR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ivx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ivx OCA], [http://pdbe.org/6ivx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ivx RCSB], [http://www.ebi.ac.uk/pdbsum/6ivx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ivx ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Adachi, T]]
 [[Category: Doi, S]]

6ivx

From Proteopedia

Revision as of 12:44, 13 March 2019

Discovery of the Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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