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4x2i

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Revision as of 13:48, 16 November 2017

Discovery of benzotriazolo diazepines as orally-active inhibitors of BET bromodomains: Crystal structure of BRD4 with CPI-13

Structural highlights

4x2i is a 1 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:	BRD4, HUNK1 (HUMAN)
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

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.,Taylor AM, Vaswani RG, Gehling VS, Hewitt MC, Leblanc Y, Audia JE, Bellon S, Cummings RT, Cote A, Harmange JC, Jayaram H, Joshi S, Lora JM, Mertz JA, Neiss A, Pardo E, Nasveschuk CG, Poy F, Sandy P, Setser JW, Sims RJ 3rd, Tang Y, Albrecht BK ACS Med Chem Lett. 2015 Mar 25;7(2):145-50. doi: 10.1021/ml500411h. eCollection, 2016 Feb 11. PMID:26985289^[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
↑ Taylor AM, Vaswani RG, Gehling VS, Hewitt MC, Leblanc Y, Audia JE, Bellon S, Cummings RT, Cote A, Harmange JC, Jayaram H, Joshi S, Lora JM, Mertz JA, Neiss A, Pardo E, Nasveschuk CG, Poy F, Sandy P, Setser JW, Sims RJ 3rd, Tang Y, Albrecht BK. Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains. ACS Med Chem Lett. 2015 Mar 25;7(2):145-50. doi: 10.1021/ml500411h. eCollection, 2016 Feb 11. PMID:26985289 doi:http://dx.doi.org/10.1021/ml500411h

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4x2i"

@@ Line 3: / Line 3: @@
 <StructureSection load='4x2i' size='340' side='right' caption='[[4x2i]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4x2i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X2I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X2I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4x2i]] 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=4X2I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X2I FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3X0:(4R)-6-(4-CHLOROPHENYL)-1,4-DIMETHYL-5,6-DIHYDRO-4H-[1,2,4]TRIAZOLO[4,3-A][1,5]BENZODIAZEPINE'>3X0</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></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=4x2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x2i OCA], [http://pdbe.org/4x2i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x2i RCSB], [http://www.ebi.ac.uk/pdbsum/4x2i PDBsum]</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=4x2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x2i OCA], [http://pdbe.org/4x2i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x2i RCSB], [http://www.ebi.ac.uk/pdbsum/4x2i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x2i ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 4x2i" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Bromodomain-containing protein|Bromodomain-containing protein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Bellon, S F]]
 [[Category: Jayaram, H]]

4x2i

From Proteopedia

Revision as of 13:48, 16 November 2017

Discovery of benzotriazolo diazepines as orally-active inhibitors of BET bromodomains: Crystal structure of BRD4 with CPI-13

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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