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[[Image: | ==4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER== | ||
<StructureSection load='2vci' size='340' side='right' caption='[[2vci]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vci]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VCI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VCI FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2GJ:5-[2,4-DIHYDROXY-5-(1-METHYLETHYL)PHENYL]-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE'>2GJ</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1osf|1osf]], [[1uy8|1uy8]], [[1uy9|1uy9]], [[1uyd|1uyd]], [[1uye|1uye]], [[1uyh|1uyh]], [[1uyi|1uyi]], [[1uyl|1uyl]], [[1yc4|1yc4]], [[2bt0|2bt0]], [[2bug|2bug]], [[2byh|2byh]], [[2bz5|2bz5]], [[2c2l|2c2l]], [[2ccs|2ccs]], [[2cct|2cct]], [[2ccu|2ccu]], [[2cdd|2cdd]], [[2uwd|2uwd]], [[1byq|1byq]], [[1uy6|1uy6]], [[1uy7|1uy7]], [[1uyc|1uyc]], [[1uyf|1uyf]], [[1uyg|1uyg]], [[1uyk|1uyk]], [[1yc1|1yc1]], [[1yc3|1yc3]], [[2bsm|2bsm]], [[2byi|2byi]], [[2vcj|2vcj]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vci OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vci RCSB], [http://www.ebi.ac.uk/pdbsum/2vci PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vc/2vci_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:18020435</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Heat Shock Proteins|Heat Shock Proteins]] | *[[Heat Shock Proteins|Heat Shock Proteins]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Aherne, W.]] | [[Category: Aherne, W.]] | ||
Revision as of 12:26, 29 September 2014
4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER
Structural highlights
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 PubMedInhibitors 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Homo sapiens
- Aherne, W.
- Barril, X.
- Borgognoni, J.
- Boxal, K.
- Brough, P A.
- Cansfield, J E.
- Cheung, K M.
- Collins, I.
- Davies, N G.M.
- Drysdale, M J.
- Dymock, B.
- Eccles, S A.
- Finch, H.
- Fink, A.
- Hayes, A.
- Howes, R.
- Hubbard, R E.
- James, K.
- Jordan, A M.
- Lockie, A.
- Martins, V.
- Massey, A.
- Matthews, T P.
- Mcdonald, E.
- Northfield, C J.
- Pearl, L H.
- Prodromou, C.
- Ray, S.
- Raynaud, F I.
- Roughley, S D.
- Sharp, S Y.
- Surgenor, A.
- Walmsley, D L.
- Webb, P.
- Wood, M.
- Workman, P.
- Wright, L.
- Atp-binding
- Chaperone
- Nucleotide-binding
- Phosphorylation
- Stress response