5s9q - Revision history

OCA at 09:59, 22 May 2024

2024-05-22T09:59:04Z

←Older revision		Revision as of 09:59, 22 May 2024
Line 12:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).		[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
		+
		+	Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.,Gavai AV, Norris D, Delucca G, Tortolani D, Tokarski JS, Dodd D, O'Malley D, Zhao Y, Quesnelle C, Gill P, Vaccaro W, Huynh T, Ahuja V, Han WC, Mussari C, Harikrishnan L, Kamau M, Poss M, Sheriff S, Yan C, Marsilio F, Menard K, Wen ML, Rampulla R, Wu DR, Li J, Zhang H, Li P, Sun D, Yip H, Traeger SC, Zhang Y, Mathur A, Zhang H, Huang C, Yang Z, Ranasinghe A, Everlof G, Raghavan N, Tye CK, Wee S, Hunt JT, Vite G, Westhouse R, Lee FY J Med Chem. 2021 Oct 14;64(19):14247-14265. doi: 10.1021/acs.jmedchem.1c00625., Epub 2021 Sep 20. PMID:34543572<ref>PMID:34543572</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5s9q" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 15:28, 6 March 2024

2024-03-06T15:28:42Z

←Older revision		Revision as of 15:28, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='5s9q' size='340' side='right'caption='[[5s9q]], [[Resolution\|resolution]] 1.85Å' scene=''>		<StructureSection load='5s9q' size='340' side='right'caption='[[5s9q]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5s9q]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5S9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5S9Q FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5s9q]] 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=5S9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5S9Q FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=YW7:2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide'>YW7</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]] 1.85Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=YW7:2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide'>YW7</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=5s9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5s9q OCA], [https://pdbe.org/5s9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5s9q RCSB], [https://www.ebi.ac.uk/pdbsum/5s9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5s9q 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=5s9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5s9q OCA], [https://pdbe.org/5s9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5s9q RCSB], [https://www.ebi.ac.uk/pdbsum/5s9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5s9q ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>	+	[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).	+	[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.	+
-		+
-	Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.,Gavai AV, Norris D, Delucca G, Tortolani D, Tokarski JS, Dodd D, O'Malley D, Zhao Y, Quesnelle C, Gill P, Vaccaro W, Huynh T, Ahuja V, Han WC, Mussari C, Harikrishnan L, Kamau M, Poss M, Sheriff S, Yan C, Marsilio F, Menard K, Wen ML, Rampulla R, Wu DR, Li J, Zhang H, Li P, Sun D, Yip H, Traeger SC, Zhang Y, Mathur A, Zhang H, Huang C, Yang Z, Ranasinghe A, Everlof G, Raghavan N, Tye CK, Wee S, Hunt JT, Vite G, Westhouse R, Lee FY J Med Chem. 2021 Oct 14;64(19):14247-14265. doi: 10.1021/acs.jmedchem.1c00625., Epub 2021 Sep 20. PMID:34543572<ref>PMID:34543572</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5s9q" style="background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Sheriff, S]]	+	[[Category: Sheriff S]]
-	~~[[Category: Brd4]]~~	+
-	~~[[Category: Bromodomain containing protein 4]]~~	+
-	~~[[Category: Bromodomain-containing protein 4 isoform long]]~~	+
-	~~[[Category: Cap]]~~	+
-	~~[[Category: Cell cycle]]~~	+
-	~~[[Category: Hunk1]]~~	+
-	~~[[Category: Mcap]]~~	+
-	~~[[Category: Mitotic chromosome associated protein sgc~~]]	+

OCA at 14:06, 17 November 2021

2021-11-17T14:06:43Z

←Older revision		Revision as of 14:06, 17 November 2021
Line 1:		Line 1:

	==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide==		==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide==
-	<StructureSection load='5s9q' size='340' side='right'caption='[[5s9q]]' scene=''>	+	<StructureSection load='5s9q' size='340' side='right'caption='[[5s9q]], [[Resolution\|resolution]] 1.85Å' 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=5S9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5S9Q FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5s9q]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5S9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5S9Q FirstGlance]. <br>
-	</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=5s9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5s9q OCA], [https://pdbe.org/5s9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5s9q RCSB], [https://www.ebi.ac.uk/pdbsum/5s9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5s9q ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=YW7:2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide'>YW7</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=5s9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5s9q OCA], [https://pdbe.org/5s9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5s9q RCSB], [https://www.ebi.ac.uk/pdbsum/5s9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5s9q ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
		+
		+	Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.,Gavai AV, Norris D, Delucca G, Tortolani D, Tokarski JS, Dodd D, O'Malley D, Zhao Y, Quesnelle C, Gill P, Vaccaro W, Huynh T, Ahuja V, Han WC, Mussari C, Harikrishnan L, Kamau M, Poss M, Sheriff S, Yan C, Marsilio F, Menard K, Wen ML, Rampulla R, Wu DR, Li J, Zhang H, Li P, Sun D, Yip H, Traeger SC, Zhang Y, Mathur A, Zhang H, Huang C, Yang Z, Ranasinghe A, Everlof G, Raghavan N, Tye CK, Wee S, Hunt JT, Vite G, Westhouse R, Lee FY J Med Chem. 2021 Oct 14;64(19):14247-14265. doi: 10.1021/acs.jmedchem.1c00625., Epub 2021 Sep 20. PMID:34543572<ref>PMID:34543572</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5s9q" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Sheriff S]]	+	[[Category: Sheriff, S]]
		+	[[Category: Brd4]]
		+	[[Category: Bromodomain containing protein 4]]
		+	[[Category: Bromodomain-containing protein 4 isoform long]]
		+	[[Category: Cap]]
		+	[[Category: Cell cycle]]
		+	[[Category: Hunk1]]
		+	[[Category: Mcap]]
		+	[[Category: Mitotic chromosome associated protein sgc]]

OCA at 08:47, 29 September 2021

2021-09-29T08:47:18Z

←Older revision		Revision as of 08:47, 29 September 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 5s9q is ON HOLD until Paper Publication~~	+	==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide==
-		+	<StructureSection load='5s9q' size='340' side='right'caption='[[5s9q]]' scene=''>
-	~~Authors: Sheriff, S.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5S9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5S9Q FirstGlance]. <br>
-	~~Description:~~ CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide	+	</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=5s9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5s9q OCA], [https://pdbe.org/5s9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5s9q RCSB], [https://www.ebi.ac.uk/pdbsum/5s9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5s9q ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Sheriff, S]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Sheriff S]]

OCA at 04:07, 28 April 2021

2021-04-28T04:07:27Z

←Older revision		Revision as of 04:07, 28 April 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5s9q is ON HOLD	+	The entry 5s9q is ON HOLD until Paper Publication

	Authors: Sheriff, S.		Authors: Sheriff, S.

OCA: Protected "5s9q" [edit=sysop:move=sysop]

2021-04-07T04:23:11Z

Protected "5s9q" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:23, 7 April 2021

OCA: New page: '''Unreleased structure''' The entry 5s9q is ON HOLD Authors: Sheriff, S. Description: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxaz...

2021-04-07T04:23:10Z

New page: '''Unreleased structure''' The entry 5s9q is ON HOLD Authors: Sheriff, S. Description: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxaz...

New page

'''Unreleased structure'''

The entry 5s9q is ON HOLD

Authors: Sheriff, S.

Description: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide
[[Category: Unreleased Structures]]
[[Category: Sheriff, S]]