OCA at 09:06, 5 February 2020

OCA — Wed, 05 Feb 2020 09:06:59 GMT

←Older revision		Revision as of 09:06, 5 February 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6tq1 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1,3-dimethoxypropan-2-yl)-5-morpholino-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one==
		+	<StructureSection load='6tq1' size='340' side='right'caption='[[6tq1]], [[Resolution\|resolution]] 1.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6tq1]] is a 3 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=6TQ1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TQ1 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NUH:5-(3-methoxyphenyl)-1-methyl-pyridin-2-one'>NUH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BRD2, KIAA9001, RING3 ([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=6tq1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tq1 OCA], [http://pdbe.org/6tq1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tq1 RCSB], [http://www.ebi.ac.uk/pdbsum/6tq1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tq1 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN]] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

-	~~Authors:~~ Chung, C.	+	Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.,Wellaway CR, Amans D, Bamborough P, Barnett H, Bit RA, Brown JA, Carlson NR, Chung CW, Cooper AWJ, Craggs PD, Davis RP, Dean TW, Evans JP, Gordon L, Harada IL, Hirst DJ, Humphreys PG, Jones KL, Lewis AJ, Lindon MJ, Lugo D, Mahmood M, McCleary S, Medeiros P, Mitchell DJ, O'Sullivan M, Le Gall A, Patel VK, Patten C, Poole DL, Shah RR, Smith JE, Stafford KAJ, Thomas PJ, Vimal M, Wall ID, Watson RJ, Wellaway N, Yao G, Prinjha RK J Med Chem. 2020 Jan 23;63(2):714-746. doi: 10.1021/acs.jmedchem.9b01670. Epub, 2020 Jan 6. PMID:31904959<ref>PMID:31904959</ref>

-	~~Description: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1~~,3-~~dimethoxypropan~~-~~2-yl)-5-morpholino-1H-benzo~~[d]~~imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6tq1" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Chung, C]]		[[Category: Chung, C]]
		+	[[Category: Antagonist]]
		+	[[Category: Brd4]]
		+	[[Category: Bromodomain]]
		+	[[Category: Bromodomain containing protein 4]]
		+	[[Category: Epigenetic reader]]
		+	[[Category: Histone]]
		+	[[Category: Inhibitor]]
		+	[[Category: Transcription]]

OCA: Protected "6tq1" [edit=sysop:move=sysop]

OCA — Wed, 25 Dec 2019 07:20:55 GMT

Protected "6tq1" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:20, 25 December 2019

OCA: New page: '''Unreleased structure''' The entry 6tq1 is ON HOLD until Paper Publication Authors: Chung, C. Description: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1,3-dimethoxypropan-2-yl)-5...

OCA — Wed, 25 Dec 2019 07:20:53 GMT

New page: '''Unreleased structure''' The entry 6tq1 is ON HOLD until Paper Publication Authors: Chung, C. Description: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1,3-dimethoxypropan-2-yl)-5...

New page

'''Unreleased structure'''

The entry 6tq1 is ON HOLD until Paper Publication

Authors: Chung, C.

Description: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1,3-dimethoxypropan-2-yl)-5-morpholino-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one
[[Category: Unreleased Structures]]
[[Category: Chung, C]]

6tq1 - Revision history

OCA at 09:06, 5 February 2020

OCA: Protected "6tq1" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6tq1 is ON HOLD until Paper Publication Authors: Chung, C. Description: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-(1-(1,3-dimethoxypropan-2-yl)-5...