5xxh: Difference between revisions
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==Crystal Structure Analysis of the CBP== | |||
<StructureSection load='5xxh' size='340' side='right' caption='[[5xxh]], [[Resolution|resolution]] 1.62Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5xxh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XXH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XXH FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E0D:(3S)-1-[2-(3-ethanoylindol-1-yl)ethanoyl]piperidine-3-carboxylic+acid'>E0D</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </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=5xxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xxh OCA], [http://pdbe.org/5xxh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xxh RCSB], [http://www.ebi.ac.uk/pdbsum/5xxh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xxh ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://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:[http://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 == | |||
[[http://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 == | |||
The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization. The most potent compound 32h binds to the CBP bromodomain and has an IC50 value of 0.037muM in the AlphaScreen assay which was 2 times more potent than the reported CBP bromodomain inhibitor SGC-CBP30 in our hands. 32h also exhibit high selectivity for CBP/EP300 over other bromodomain-containing proteins. Notably, the ester derivative (29h) of compound 32h markedly inhibits cell growth in several prostate cancer cell lines including LNCaP, 22Rv1 and LNCaP derived C4-2B. Compound 29h suppresses the mRNA expression of full length AR (AR-FL), AR target genes and other oncogene in LNCaP cells. 29h also reduces the expression of PSA, the biomarker of prostate cancer. CBP/EP300 inhibitor 29h represents a promising lead compound for the development of new therapeutics for the treatment of castration-resistant prostate cancer. | |||
Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer.,Xiang Q, Wang C, Zhang Y, Xue X, Song M, Zhang C, Li C, Wu C, Li K, Hui X, Zhou Y, Smaill JB, Patterson AV, Wu D, Ding K, Xu Y Eur J Med Chem. 2018 Mar 10;147:238-252. doi: 10.1016/j.ejmech.2018.01.087. Epub , 2018 Feb 6. PMID:29448139<ref>PMID:29448139</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5xxh" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Histone acetyltransferase]] | |||
[[Category: Song, M]] | |||
[[Category: Wang, C]] | |||
[[Category: Xiang, Q]] | [[Category: Xiang, Q]] | ||
[[Category: Zhang, Y]] | [[Category: Zhang, Y]] | ||
[[Category: | [[Category: Bromodomain]] | ||
[[Category: | [[Category: Cbp]] | ||
[[Category: Transferase]] | |||