6fyz

From Proteopedia

(Difference between revisions)

Current revision

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Structural highlights

6fyz is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	HDAC4, KIAA0288 (HUMAN)
Activity:	Histone deacetylase, with EC number 3.5.1.98
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM: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.^[1]

Function

[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.^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, Zondag S, Toriello HV, Magenis RE, Elsea SH. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010 Aug 13;87(2):219-28. doi: 10.1016/j.ajhg.2010.07.011. PMID:20691407 doi:10.1016/j.ajhg.2010.07.011
↑ Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol. 1999 Nov;19(11):7816-27. PMID:10523670
↑ 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. Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Bioorg Med Chem Lett. 2018 Nov 13. pii: S0960-894X(18)30858-8. doi:, 10.1016/j.bmcl.2018.11.009. PMID:30463802 doi:http://dx.doi.org/10.1016/j.bmcl.2018.11.009

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fyz"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fyz' size='340' side='right' caption='[[6fyz]], [[Resolution|resolution]] 2.15&Aring;' 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>
+<table><tr><td colspan='2'>[[6fyz]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HDAC4, KIAA0288 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
@@ Line 26: / Line 27: @@
 </StructureSection>
 [[Category: Histone deacetylase]]
+[[Category: Human]]
 [[Category: Dominguez, C]]
 [[Category: Luckhurst, C A]]

6fyz

From Proteopedia

Current revision

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox