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5d0c

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Crystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand

Structural highlights

5d0c 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.
Method:	X-ray diffraction, Resolution 1.49Å
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

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation.,Xue X, Zhang Y, Liu Z, Song M, Xing Y, Xiang Q, Wang Z, Tu Z, Zhou Y, Ding K, Xu Y J Med Chem. 2016 Jan 12. PMID:26731490^[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
↑ Xue X, Zhang Y, Liu Z, Song M, Xing Y, Xiang Q, Wang Z, Tu Z, Zhou Y, Ding K, Xu Y. Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation. J Med Chem. 2016 Jan 12. PMID:26731490 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01511

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/5d0c"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5d0c]] 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=5D0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5D0C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E0B:N-[(1-ACETYLPIPERIDIN-4-YL)METHYL]-1-ETHYL-2-OXO-1,2-DIHYDROBENZO[CD]INDOLE-6-SULFONAMIDE'>E0B</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 1.49&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E0B:N-[(1-ACETYLPIPERIDIN-4-YL)METHYL]-1-ETHYL-2-OXO-1,2-DIHYDROBENZO[CD]INDOLE-6-SULFONAMIDE'>E0B</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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=5d0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5d0c OCA], [https://pdbe.org/5d0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5d0c RCSB], [https://www.ebi.ac.uk/pdbsum/5d0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5d0c ProSAT]</span></td></tr>
 </table>

5d0c

From Proteopedia

Current revision

Crystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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