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2vcj

From Proteopedia

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4,5 Diaryl Isoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

Structural highlights

2vcj is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.,Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L J Med Chem. 2008 Jan 24;51(2):196-218. Epub 2007 Nov 20. PMID:18020435^[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
↑ Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 2008 Jan 24;51(2):196-218. Epub 2007 Nov 20. PMID:18020435 doi:10.1021/jm701018h

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2vcj"

@@ Line 3: / Line 3: @@
 <StructureSection load='2vcj' size='340' side='right'caption='[[2vcj]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2vcj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VCJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2vcj]] 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=2VCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VCJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2EQ:5-(5-CHLORO-2,4-DIHYDROXYPHENYL)-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE'>2EQ</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2cdd|2cdd]], [[1uy9|1uy9]], [[1uy6|1uy6]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[1yc4|1yc4]], [[1uy8|1uy8]], [[2bug|2bug]], [[2uwd|2uwd]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[1uyh|1uyh]], [[2cct|2cct]], [[2bt0|2bt0]], [[1uyg|1uyg]], [[1uye|1uye]], [[1uyl|1uyl]], [[2ccu|2ccu]], [[2bz5|2bz5]], [[1yc1|1yc1]], [[2ccs|2ccs]], [[1uyc|1uyc]], [[1uy7|1uy7]], [[1yc3|1yc3]], [[1uyf|1uyf]], [[1uyi|1uyi]], [[2byh|2byh]], [[1uyd|1uyd]], [[2byi|2byi]], [[2vci|2vci]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2EQ:5-(5-CHLORO-2,4-DIHYDROXYPHENYL)-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE'>2EQ</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vcj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vcj OCA], [https://pdbe.org/2vcj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vcj RCSB], [https://www.ebi.ac.uk/pdbsum/2vcj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vcj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/HS90A_HUMAN 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.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
+[https://www.uniprot.org/uniprot/HS90A_HUMAN 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.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Aherne, W]]
+[[Category: Aherne W]]
-[[Category: Barril, X]]
+[[Category: Barril X]]
-[[Category: Borgognoni, J]]
+[[Category: Borgognoni J]]
-[[Category: Boxal, K]]
+[[Category: Boxal K]]
-[[Category: Brough, P A]]
+[[Category: Brough PA]]
-[[Category: Cansfield, J E]]
+[[Category: Cansfield JE]]
-[[Category: Cheung, K M]]
+[[Category: Cheung KM]]
-[[Category: Collins, I]]
+[[Category: Collins I]]
-[[Category: Davies, N G.M]]
+[[Category: Davies NGM]]
-[[Category: Drysdale, M J]]
+[[Category: Drysdale MJ]]
-[[Category: Dymock, B]]
+[[Category: Dymock B]]
-[[Category: Eccles, S A]]
+[[Category: Eccles SA]]
-[[Category: Finch, H]]
+[[Category: Finch H]]
-[[Category: Fink, A]]
+[[Category: Fink A]]
-[[Category: Hayes, A]]
+[[Category: Hayes A]]
-[[Category: Howes, R]]
+[[Category: Howes R]]
-[[Category: Hubbard, R E]]
+[[Category: Hubbard RE]]
-[[Category: James, K]]
+[[Category: James K]]
-[[Category: Jordan, A M]]
+[[Category: Jordan AM]]
-[[Category: Lockie, A]]
+[[Category: Lockie A]]
-[[Category: Martins, V]]
+[[Category: Martins V]]
-[[Category: Massey, A]]
+[[Category: Massey A]]
-[[Category: Matthews, T P]]
+[[Category: Matthews TP]]
-[[Category: McDonald, E]]
+[[Category: McDonald E]]
-[[Category: Northfield, C J]]
+[[Category: Northfield CJ]]
-[[Category: Pearl, L H]]
+[[Category: Pearl LH]]
-[[Category: Prodromou, C]]
+[[Category: Prodromou C]]
-[[Category: Ray, S]]
+[[Category: Ray S]]
-[[Category: Raynaud, F I]]
+[[Category: Raynaud FI]]
-[[Category: Roughley, S D]]
+[[Category: Roughley SD]]
-[[Category: Sharp, S Y]]
+[[Category: Sharp SY]]
-[[Category: Surgenor, A]]
+[[Category: Surgenor A]]
-[[Category: Walmsley, D L]]
+[[Category: Walmsley DL]]
-[[Category: Webb, P]]
+[[Category: Webb P]]
-[[Category: Wood, M]]
+[[Category: Wood M]]
-[[Category: Workman, P]]
+[[Category: Workman P]]
-[[Category: Wright, L]]
+[[Category: Wright L]]
-[[Category: Alternative splicing]]
-[[Category: Atp-binding]]
-[[Category: Chaperone]]
-[[Category: Cytoplasm]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphorylation]]
-[[Category: Stress response]]

2vcj

From Proteopedia

Current revision

4,5 Diaryl Isoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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