OCA at 08:18, 11 October 2023

OCA — Wed, 11 Oct 2023 08:18:59 GMT

←Older revision		Revision as of 08:18, 11 October 2023
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	==Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt==		==Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt==
-	<StructureSection load='6vsw' size='340' side='right'caption='[[6vsw]]' scene=''>	+	<StructureSection load='6vsw' size='340' side='right'caption='[[6vsw]], [[Resolution\|resolution]] 3.20Å' 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=6VSW OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6VSW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6vsw]] 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=6VSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VSW FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6vsw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vsw OCA], [~~http~~://pdbe.org/6vsw PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6vsw RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6vsw PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6vsw 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]] 3.202Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RG7:5-(2,3-dichloro-4-{[(2S)-1,1,1-trifluoropropan-2-yl]sulfamoyl}phenyl)-4-(4-fluoropiperidine-1-carbonyl)-N-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-carboxamide'>RG7</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=6vsw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vsw OCA], [https://pdbe.org/6vsw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vsw RCSB], [https://www.ebi.ac.uk/pdbsum/6vsw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vsw ProSAT]</span></td></tr>
	</table>		</table>
		+	== 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;">
		+	== Publication Abstract from PubMed ==
		+	The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORgammat) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORgammat lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORgammat drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORgammat inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORgammat was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORgammat inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
		+
		+	Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgammat.,Gege C, Albers M, Kinzel O, Kleymann G, Schluter T, Steeneck C, Hoffmann T, Xue X, Cummings MD, Spurlino J, Milligan C, Fourie AM, Edwards JP, Leonard K, Coe K, Scott B, Pippel D, Goldberg SD Bioorg Med Chem Lett. 2020 Jun 15;30(12):127205. doi: 10.1016/j.bmcl.2020.127205., Epub 2020 Apr 21. PMID:32336498<ref>PMID:32336498</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6vsw" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Milligan C]]		[[Category: Milligan C]]
	[[Category: Spurlino J]]		[[Category: Spurlino J]]

OCA at 05:34, 13 May 2020

OCA — Wed, 13 May 2020 05:34:40 GMT

←Older revision		Revision as of 05:34, 13 May 2020
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-	'''Unreleased structure'''

-	~~The entry 6vsw is ON HOLD until Paper Publication~~	+	==Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt==
-		+	<StructureSection load='6vsw' size='340' side='right'caption='[[6vsw]]' scene=''>
-	~~Authors: Spurlino, J., Milligan, C.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VSW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VSW FirstGlance]. <br>
-	~~Description:~~ Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vsw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vsw OCA], [http://pdbe.org/6vsw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vsw RCSB], [http://www.ebi.ac.uk/pdbsum/6vsw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vsw ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Milligan, C]]	+	__TOC__
-	[[Category: Spurlino, J]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Milligan C]]
		+	[[Category: Spurlino J]]

OCA at 08:26, 18 March 2020

OCA — Wed, 18 Mar 2020 08:26:54 GMT

←Older revision		Revision as of 08:26, 18 March 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6vsw is ON HOLD	+	The entry 6vsw is ON HOLD until Paper Publication

	Authors: Spurlino, J., Milligan, C.		Authors: Spurlino, J., Milligan, C.

OCA: Protected "6vsw" [edit=sysop:move=sysop]

OCA — Wed, 19 Feb 2020 05:21:24 GMT

Protected "6vsw" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:21, 19 February 2020

OCA: New page: '''Unreleased structure''' The entry 6vsw is ON HOLD Authors: Spurlino, J., Milligan, C. Description: Optimization and biological evaluation of thiazole-bis-amide inverse agonists of R...

OCA — Wed, 19 Feb 2020 05:21:23 GMT

New page: '''Unreleased structure''' The entry 6vsw is ON HOLD Authors: Spurlino, J., Milligan, C. Description: Optimization and biological evaluation of thiazole-bis-amide inverse agonists of R...

New page

'''Unreleased structure'''

The entry 6vsw is ON HOLD

Authors: Spurlino, J., Milligan, C.

Description: Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt
[[Category: Unreleased Structures]]
[[Category: Milligan, C]]
[[Category: Spurlino, J]]

6vsw - Revision history

OCA at 08:18, 11 October 2023

OCA at 05:34, 13 May 2020

OCA at 08:26, 18 March 2020

OCA: Protected "6vsw" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6vsw is ON HOLD Authors: Spurlino, J., Milligan, C. Description: Optimization and biological evaluation of thiazole-bis-amide inverse agonists of R...