View source for 7evj


==Crystal structure of CBP bromodomain liganded with 9c==
<StructureSection load='7evj' size='340' side='right'caption='[[7evj]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7evj]] 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=7EVJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EVJ 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]] 2.57&#8491;</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=JE9:3-acetyl-1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-5-(hydroxymethyl)phenyl)carbamoyl)indolizin-7-yl+dimethylcarbamate'>JE9</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7evj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7evj OCA], [https://pdbe.org/7evj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7evj RCSB], [https://www.ebi.ac.uk/pdbsum/7evj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7evj ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription.  Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:[https://omim.org/entry/180849 180849]. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.<ref>PMID:11331617</ref> <ref>PMID:12114483</ref> <ref>PMID:12566391</ref> <ref>PMID:15706485</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref> <ref>PMID:11154691</ref> <ref>PMID:12738767</ref> <ref>PMID:12929931</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.

Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer.,Xiang Q, Wang C, Wu T, Zhang C, Hu Q, Luo G, Hu J, Zhuang X, Zou L, Shen H, Wu X, Zhang Y, Kong X, Liu J, Xu Y J Med Chem. 2022 Jan 13;65(1):785-810. doi: 10.1021/acs.jmedchem.1c01864. Epub, 2021 Dec 28. PMID:34962793<ref>PMID:34962793</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7evj" style="background-color:#fffaf0;"></div>

==See Also==
*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Luo G]]
[[Category: Shen H]]
[[Category: Wang C]]
[[Category: Wu T]]
[[Category: Wu X]]
[[Category: Xiang Q]]
[[Category: Xu Y]]
[[Category: Zhang C]]
[[Category: Zhang Y]]