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4hxl

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Revision as of 08:24, 9 November 2022

Brd4 Bromodomain 1 complex with 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE inhibitor

Structural highlights

4hxl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

Recognizing acetyllysine of histone is a vital process of epigenetic regulations, which is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them, and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype as well as other fragment hits described herein, can stimulate researchers to develop more diversified bromodomain inhibitors.

Fragment-based Drug Discovery of 2-thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.,Zhao L, Cao D, Chen T, Wang Y, Miao ZH, Xu Y, Chen W, Wang X, Li Y, Du Z, Xiong B, Li J, Xu C, Zhang N, He J, Shen J J Med Chem. 2013 Mar 26. PMID:23530754^[3]

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

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Zhao L, Cao D, Chen T, Wang Y, Miao ZH, Xu Y, Chen W, Wang X, Li Y, Du Z, Xiong B, Li J, Xu C, Zhang N, He J, Shen J. Fragment-based Drug Discovery of 2-thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain. J Med Chem. 2013 Mar 26. PMID:23530754 doi:10.1021/jm301793a

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4hxl"

@@ Line 1: / Line 1: @@
 ==Brd4 Bromodomain 1 complex with 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE inhibitor==
-<StructureSection load='4hxl' size='340' side='right' caption='[[4hxl]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
+<StructureSection load='4hxl' size='340' side='right'caption='[[4hxl]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4hxl]] is a 1 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=4HXL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HXL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4hxl]] 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=4HXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HXL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1A9:3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE'>1A9</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1A9:3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE'>1A9</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hxk|4hxk]], [[4hxm|4hxm]], [[4hxn|4hxn]], [[4hxo|4hxo]], [[4hxp|4hxp]], [[4hxr|4hxr]], [[4hxs|4hxs]]</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=4hxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hxl OCA], [https://pdbe.org/4hxl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hxl RCSB], [https://www.ebi.ac.uk/pdbsum/4hxl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hxl ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([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=4hxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hxl OCA], [http://pdbe.org/4hxl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hxl RCSB], [http://www.ebi.ac.uk/pdbsum/4hxl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hxl ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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 ==
-[[http://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 ==
@@ Line 24: / Line 22: @@
 ==See Also==
-*[[Bromodomain-containing protein|Bromodomain-containing protein]]
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Cao, D Y]]
+[[Category: Large Structures]]
-[[Category: Chen, T T]]
+[[Category: Cao DY]]
-[[Category: Chen, W Y]]
+[[Category: Chen TT]]
-[[Category: Shen, J K]]
+[[Category: Chen WY]]
-[[Category: Xiong, B]]
+[[Category: Shen JK]]
-[[Category: Xu, Y C]]
+[[Category: Xiong B]]
-[[Category: Brd4]]
+[[Category: Xu YC]]
-[[Category: Bromodomain]]
-[[Category: Four alpha helice]]
-[[Category: Protein binding-inhibitor complex]]

4hxl

From Proteopedia

Revision as of 08:24, 9 November 2022

Brd4 Bromodomain 1 complex with 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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