8wy3: Difference between revisions

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'''Unreleased structure'''


The entry 8wy3 is ON HOLD  until Paper Publication
==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21==
<StructureSection load='8wy3' size='340' side='right'caption='[[8wy3]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8wy3]] is a 3 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=8WY3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WY3 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.78&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XHE:~{N}-cyclopropyl-2-[[5-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-1-methyl-2-oxidanylidene-pyridin-4-yl]amino]ethanamide'>XHE</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=8wy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wy3 OCA], [https://pdbe.org/8wy3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wy3 RCSB], [https://www.ebi.ac.uk/pdbsum/8wy3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wy3 ProSAT]</span></td></tr>
</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 ==
Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC(50) = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC(50) = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC(50) &gt; 30 muM) mitigated the inhibition of the human ether-a-go-go-related gene (hERG) ion channel compared with 10 (hERG IC(50) = 2.8 muM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.


Authors: Xu, H., Zhao, X., Shen, H., Xu, Y., Wu, X.
Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.,Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X J Med Chem. 2024 Jan 4. doi: 10.1021/acs.jmedchem.3c02104. PMID:38175809<ref>PMID:38175809</ref>


Description: Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Wu, X]]
<div class="pdbe-citations 8wy3" style="background-color:#fffaf0;"></div>
[[Category: Zhao, X]]
== References ==
[[Category: Xu, H]]
<references/>
[[Category: Shen, H]]
__TOC__
[[Category: Xu, Y]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Shen H]]
[[Category: Wu X]]
[[Category: Xu H]]
[[Category: Xu Y]]
[[Category: Zhao X]]

Revision as of 14:31, 24 January 2024

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21

Structural highlights

8wy3 is a 3 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 2.78Å
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

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC(50) = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC(50) = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC(50) > 30 muM) mitigated the inhibition of the human ether-a-go-go-related gene (hERG) ion channel compared with 10 (hERG IC(50) = 2.8 muM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.,Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X J Med Chem. 2024 Jan 4. doi: 10.1021/acs.jmedchem.3c02104. PMID:38175809[3]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X. Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia. J Med Chem. 2024 Jan 4. PMID:38175809 doi:10.1021/acs.jmedchem.3c02104

8wy3, resolution 2.78Å

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