5eu1: Difference between revisions
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==CRYSTAL STRUCTURE OF BRD9 IN COMPLEX WITH BI-7273== | |||
<StructureSection load='5eu1' size='340' side='right' caption='[[5eu1]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5eu1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EU1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EU1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5SW:4-[4-[(DIMETHYLAMINO)METHYL]-3,5-DIMETHOXY-PHENYL]-2-METHYL-2,7-NAPHTHYRIDIN-1-ONE'>5SW</scene></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=5eu1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eu1 OCA], [http://pdbe.org/5eu1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eu1 RCSB], [http://www.ebi.ac.uk/pdbsum/5eu1 PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BRD9_HUMAN BRD9_HUMAN]] May play a role in chromatin remodeling and regulation of transcription. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Components of the chromatin remodelling SWI/SNF complex are recurrently mutated in tumours, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold. Crystallographic information of the inhibitors bound to BRD9 guided their development with respect to potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display anti-tumour activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings. | |||
Structure-based design of an in vivo active selective BRD9 inhibitor.,Martin LJ, Koegl M, Bader G, Cockcroft XL, Fedorov O, Fiegen D, Gerstberger T, Hofmann MH, Hohmann AF, Kessler D, Knapp S, Knesl P, Kornigg S, Muller S, Nar H, Rogers C, Rumpel K, Schaaf O, Steurer S, Tallant C, Vakoc CR, Zeeb M, Zoephel A, Pearson M, Boehmelt G, McConnell D J Med Chem. 2016 Feb 25. PMID:26914985<ref>PMID:26914985</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5eu1" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bader, G]] | |||
[[Category: Martin, L M]] | |||
[[Category: Steurer, S]] | [[Category: Steurer, S]] | ||
[[Category: | [[Category: Weiss-Puxbaum, A]] | ||
[[Category: Zoephel, A]] | [[Category: Zoephel, A]] | ||
[[Category: | [[Category: Bromodomain]] | ||
[[Category: | [[Category: Inhibitor]] | ||
[[Category: Transcription]] | |||
Revision as of 06:40, 10 March 2016
CRYSTAL STRUCTURE OF BRD9 IN COMPLEX WITH BI-7273CRYSTAL STRUCTURE OF BRD9 IN COMPLEX WITH BI-7273
Structural highlights
Function[BRD9_HUMAN] May play a role in chromatin remodeling and regulation of transcription. Publication Abstract from PubMedComponents of the chromatin remodelling SWI/SNF complex are recurrently mutated in tumours, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold. Crystallographic information of the inhibitors bound to BRD9 guided their development with respect to potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display anti-tumour activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings. Structure-based design of an in vivo active selective BRD9 inhibitor.,Martin LJ, Koegl M, Bader G, Cockcroft XL, Fedorov O, Fiegen D, Gerstberger T, Hofmann MH, Hohmann AF, Kessler D, Knapp S, Knesl P, Kornigg S, Muller S, Nar H, Rogers C, Rumpel K, Schaaf O, Steurer S, Tallant C, Vakoc CR, Zeeb M, Zoephel A, Pearson M, Boehmelt G, McConnell D J Med Chem. 2016 Feb 25. PMID:26914985[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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