7wjs: Difference between revisions
New page: '''Unreleased structure''' The entry 7wjs is ON HOLD Authors: Li, J., Zhang, C., Xu, H., Zhuang, X., Wu, X., Zhang, Y., Xu, Y. Description: Crystal Structure of the first bromodomain o... |
No edit summary |
||
| (3 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor Y13157== | ||
<StructureSection load='7wjs' size='340' side='right'caption='[[7wjs]], [[Resolution|resolution]] 2.73Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7wjs]] 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=7WJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WJS 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]] 2.73Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JFL:2-(2-cyclobutyl-1~{H}-imidazol-5-yl)-7-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-5-methyl-furo[3,2-c]pyridin-4-one'>JFL</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=7wjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wjs OCA], [https://pdbe.org/7wjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wjs RCSB], [https://www.ebi.ac.uk/pdbsum/7wjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wjs 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 == | |||
Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML). | |||
Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.,Li J, Zhang C, Xu H, Wang C, Dong R, Shen H, Zhuang X, Chen X, Li Q, Lu J, Zhang M, Wu X, Loomes KM, Zhou Y, Zhang Y, Liu J, Xu Y J Med Chem. 2022 Apr 14;65(7):5760-5799. doi: 10.1021/acs.jmedchem.2c00100. Epub , 2022 Mar 25. PMID:35333526<ref>PMID:35333526</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7wjs" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Xu | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Zhang | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Li J]] | |||
[[Category: Wu X]] | |||
[[Category: Xu H]] | |||
[[Category: Xu Y]] | |||
[[Category: Zhang C]] | |||
[[Category: Zhang Y]] | |||
[[Category: Zhuang X]] | |||
Latest revision as of 20:41, 29 November 2023
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor Y13157Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor Y13157
Structural highlights
DiseaseBRD4_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] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedPan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML). Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.,Li J, Zhang C, Xu H, Wang C, Dong R, Shen H, Zhuang X, Chen X, Li Q, Lu J, Zhang M, Wu X, Loomes KM, Zhou Y, Zhang Y, Liu J, Xu Y J Med Chem. 2022 Apr 14;65(7):5760-5799. doi: 10.1021/acs.jmedchem.2c00100. Epub , 2022 Mar 25. PMID:35333526[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||