9j6o

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Current revision (04:21, 17 October 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 9j6o is ON HOLD until Paper Publication
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==Crystal Structure of bromodomain of human CBP in complex with the inhibitor CZL-046==
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<StructureSection load='9j6o' size='340' side='right'caption='[[9j6o]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[9j6o]] 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=9J6O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9J6O FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.67&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L3S:(3~{S},5~{S})-1-[3,4-bis(fluoranyl)phenyl]-5-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]-3-fluoranyl-pyrrolidin-2-one'>A1L3S</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9j6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9j6o OCA], [https://pdbe.org/9j6o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9j6o RCSB], [https://www.ebi.ac.uk/pdbsum/9j6o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9j6o ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC(50) = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC(50) = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.
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Authors: Zhang, Y., Zhang, C., Chen, Z., Yang, H., Huang, X., Li, Y., Xu, Y.
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Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.,Chen Z, Yang H, Zhang Y, Lyu X, Shi Q, Zhang C, Wang X, Wang Z, Zhang Y, Deng Y, Wang Y, Huang Y, Xu Y, Huang X, Li Y J Med Chem. 2024 Oct 2. doi: 10.1021/acs.jmedchem.4c01984. PMID:39356741<ref>PMID:39356741</ref>
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Description: Crystal Structure of bromodomain of human CBP in complex with the inhibitor CZL-046
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Zhang, Y]]
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<div class="pdbe-citations 9j6o" style="background-color:#fffaf0;"></div>
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[[Category: Chen, Z]]
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== References ==
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[[Category: Huang, X]]
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<references/>
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[[Category: Zhang, C]]
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__TOC__
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[[Category: Yang, H]]
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</StructureSection>
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[[Category: Xu, Y]]
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[[Category: Homo sapiens]]
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[[Category: Li, Y]]
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[[Category: Large Structures]]
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[[Category: Chen Z]]
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[[Category: Huang X]]
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[[Category: Li Y]]
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[[Category: Xu Y]]
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[[Category: Yang H]]
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[[Category: Zhang C]]
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[[Category: Zhang Y]]

Current revision

Crystal Structure of bromodomain of human CBP in complex with the inhibitor CZL-046

PDB ID 9j6o

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