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7v2j

From Proteopedia

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Current revision

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 33

Structural highlights

7v2j 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 2.24Å
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

BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with DeltaT(m) values exceeding 6 degrees C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC(50) values of 0.78 and 0.87 muM. Furthermore, 11r (0.5-10 muM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 muM) concentration-dependently blocked cell cycle in MV4-11 cells at G(0)/G(1) phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.

Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia.,Zhang MF, Luo XY, Zhang C, Wang C, Wu XS, Xiang QP, Xu Y, Zhang Y Acta Pharmacol Sin. 2022 Oct;43(10):2735-2748. doi: 10.1038/s41401-022-00881-y. , Epub 2022 Mar 9. PMID:35264812^[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
↑ Zhang MF, Luo XY, Zhang C, Wang C, Wu XS, Xiang QP, Xu Y, Zhang Y. Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia. Acta Pharmacol Sin. 2022 Oct;43(10):2735-2748. PMID:35264812 doi:10.1038/s41401-022-00881-y

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/7v2j"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7v2j]] 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=7V2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V2J FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5FZ:~{N}-(3-ethyl-6-methoxy-1,2-benzoxazol-5-yl)-4-methoxy-benzenesulfonamide'>5FZ</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]] 2.24&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5FZ:~{N}-(3-ethyl-6-methoxy-1,2-benzoxazol-5-yl)-4-methoxy-benzenesulfonamide'>5FZ</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=7v2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v2j OCA], [https://pdbe.org/7v2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v2j RCSB], [https://www.ebi.ac.uk/pdbsum/7v2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v2j ProSAT]</span></td></tr>
 </table>

7v2j

From Proteopedia

Current revision

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 33

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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