6mau
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human BRD4(1) in complex with CN210 (compound 19)== | |
| + | <StructureSection load='6mau' size='340' side='right'caption='[[6mau]], [[Resolution|resolution]] 2.11Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6mau]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MAU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MAU FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JBS:1-(4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-[(3S)-3-phenylmorpholin-4-yl]quinazolin-2-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol'>JBS</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=6mau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mau OCA], [http://pdbe.org/6mau PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mau RCSB], [http://www.ebi.ac.uk/pdbsum/6mau PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mau ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref> | ||
| + | == Function == | ||
| + | [[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 == | ||
| + | Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted. | ||
| - | + | Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases.,Yang SM, Yoshioka M, Strovel JW, Urban DJ, Hu X, Hall MD, Jadhav A, Maloney DJ Bioorg Med Chem Lett. 2019 Mar 12. pii: S0960-894X(19)30143-X. doi:, 10.1016/j.bmcl.2019.03.014. PMID:30905542<ref>PMID:30905542</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6mau" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chan, S G]] | ||
| + | [[Category: Connors, C R]] | ||
| + | [[Category: Fontano, E]] | ||
| + | [[Category: Lakshminarasimhan, D]] | ||
| + | [[Category: Nadupalli, A]] | ||
| + | [[Category: Olland, A M]] | ||
| + | [[Category: Suto, R K]] | ||
| + | [[Category: White, A]] | ||
| + | [[Category: Protein binding]] | ||
Revision as of 07:06, 3 April 2019
Crystal structure of human BRD4(1) in complex with CN210 (compound 19)
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