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4o04

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Revision as of 02:40, 5 August 2016

Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease

Structural highlights

4o04 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4o05, 4o06, 4o09, 4o0b
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.^[1] ^[2]

Publication Abstract from PubMed

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90alpha/beta inhibitors to achieve >1,000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90alpha/beta inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90alpha/beta selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90alpha/beta inhibitor was identified (compound 31) that crosses the blood brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.

Identification of novel HSP90alpha/beta isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease.,Ernst J, Neubert T, Liu M, Sperry S, Zuccola H, Turnbull A, Fleck B, Kargo W, Woody L, Chiang P, Tran D, Chen W, Snyder PW, Alcacio T, Nezami A, Reynolds J, Alvi K, Goulet L, Stamos D J Med Chem. 2014 Mar 27. PMID:24673104^[3]

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

References

↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
↑ Ernst J, Neubert T, Liu M, Sperry S, Zuccola H, Turnbull A, Fleck B, Kargo W, Woody L, Chiang P, Tran D, Chen W, Snyder PW, Alcacio T, Nezami A, Reynolds J, Alvi K, Goulet L, Stamos D. Identification of novel HSP90alpha/beta isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease. J Med Chem. 2014 Mar 27. PMID:24673104 doi:http://dx.doi.org/10.1021/jm500042s

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4o04"

Categories: Ernst, J | Zuccola, H J | Chaperone | Chaperone-chaperone inhibitor complex

@@ Line 1: / Line 1: @@
 ==Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease==
 <StructureSection load='4o04' size='340' side='right' caption='[[4o04]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2Q8:4-(2,7,7-TRIMETHYL-5-OXO-1,2,3,4,5,6,7,8-OCTAHYDRO-9H-BETA-CARBOLIN-9-YL)BENZAMIDE'>2Q8</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4o05|4o05]], [[4o06|4o06]], [[4o09|4o09]], [[4o0b|4o0b]]</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=4o04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o04 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o04 RCSB], [http://www.ebi.ac.uk/pdbsum/4o04 PDBsum]</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=4o04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o04 OCA], [http://pdbe.org/4o04 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o04 RCSB], [http://www.ebi.ac.uk/pdbsum/4o04 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o04 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4o04" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Heat Shock Proteins|Heat Shock Proteins]]
 == References ==
 <references/>

4o04

From Proteopedia

Revision as of 02:40, 5 August 2016

Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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