6fyz
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor== | |
| + | <StructureSection load='6fyz' size='340' side='right' caption='[[6fyz]], [[Resolution|resolution]] 2.15Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6fyz]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FYZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FYZ FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EBE:(2~{S})-2-(2-fluorophenyl)-2-[4-(2-methylpyrimidin-5-yl)phenyl]-~{N}-oxidanyl-ethanamide'>EBE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </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=6fyz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fyz OCA], [http://pdbe.org/6fyz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fyz RCSB], [http://www.ebi.ac.uk/pdbsum/6fyz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fyz ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[http://omim.org/entry/600430 600430]]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.<ref>PMID:20691407</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.<ref>PMID:10523670</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and approximately 150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for approximately 8h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo. | ||
| - | + | Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.,Luckhurst CA, Aziz O, Beaumont V, Burli RW, Breccia P, Maillard MC, Haughan AF, Lamers M, Leonard P, Matthews KL, Raphy G, Stott AJ, Munoz-Sanjuan I, Thomas B, Wall M, Wishart G, Yates D, Dominguez C Bioorg Med Chem Lett. 2018 Nov 13. pii: S0960-894X(18)30858-8. doi:, 10.1016/j.bmcl.2018.11.009. PMID:30463802<ref>PMID:30463802</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 6fyz" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Histone deacetylase]] | ||
[[Category: Dominguez, C]] | [[Category: Dominguez, C]] | ||
| - | [[Category: Maillard, M | + | [[Category: Luckhurst, C A]] |
| + | [[Category: Maillard, M C]] | ||
| + | [[Category: Class iia hdac inhibitor]] | ||
| + | [[Category: Cns-penetrant]] | ||
| + | [[Category: Hdac4 inhibition]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydroxamic acid]] | ||
Revision as of 06:35, 5 December 2018
Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor
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