6afr: Difference between revisions
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<StructureSection load='6afr' size='340' side='right' caption='[[6afr]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='6afr' size='340' side='right' caption='[[6afr]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6afr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AFR FirstGlance]. <br> | <table><tr><td colspan='2'>[[6afr]] 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=6AFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AFR FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9E3:5-[(4-fluoranylimidazol-1-yl)methyl]quinolin-8-ol'>9E3</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9E3:5-[(4-fluoranylimidazol-1-yl)methyl]quinolin-8-ol'>9E3</scene></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=6afr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6afr OCA], [http://pdbe.org/6afr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6afr RCSB], [http://www.ebi.ac.uk/pdbsum/6afr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6afr ProSAT]</span></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=6afr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6afr OCA], [http://pdbe.org/6afr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6afr RCSB], [http://www.ebi.ac.uk/pdbsum/6afr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6afr ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | [[http://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-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment. | |||
Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors.,Xing J, Zhang R, Jiang X, Hu T, Wang X, Qiao G, Wang J, Yang F, Luo X, Chen K, Shen J, Luo C, Jiang H, Zheng M Eur J Med Chem. 2018 Nov 16;163:281-294. doi: 10.1016/j.ejmech.2018.11.018. PMID:30529546<ref>PMID:30529546</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6afr" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Jiang, X R]] | [[Category: Jiang, X R]] | ||
[[Category: Luo, C]] | [[Category: Luo, C]] | ||
Revision as of 11:34, 26 December 2018
Crystal Structure of the first bromodomain of human BRD4 in complex with 5-((4-fluoro-1H-imidazol-1-yl)methyl)quinolin-8-olCrystal Structure of the first bromodomain of human BRD4 in complex with 5-((4-fluoro-1H-imidazol-1-yl)methyl)quinolin-8-ol
Structural highlights
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 PubMedBromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment. Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors.,Xing J, Zhang R, Jiang X, Hu T, Wang X, Qiao G, Wang J, Yang F, Luo X, Chen K, Shen J, Luo C, Jiang H, Zheng M Eur J Med Chem. 2018 Nov 16;163:281-294. doi: 10.1016/j.ejmech.2018.11.018. PMID:30529546[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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