2vcj

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[[Image:2vcj.jpg|left|200px]]
[[Image:2vcj.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2vcj |SIZE=350|CAPTION= <scene name='initialview01'>2vcj</scene>, resolution 2.50&Aring;
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The line below this paragraph, containing "STRUCTURE_2vcj", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:2eq+Binding+Site+For+Chain+A'>AC1</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=2EQ:5-(5-CHLORO-2,4-DIHYDROXYPHENYL)-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE'>2EQ</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY=
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_2vcj| PDB=2vcj | SCENE= }}
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|RELATEDENTRY=[[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]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vcj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vcj OCA], [http://www.ebi.ac.uk/pdbsum/2vcj PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2vcj RCSB]</span>
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}}
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'''4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER'''
'''4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER'''
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[[Category: Workman, P.]]
[[Category: Workman, P.]]
[[Category: Wright, L.]]
[[Category: Wright, L.]]
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[[Category: alternative splicing]]
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[[Category: Alternative splicing]]
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[[Category: atp-binding]]
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[[Category: Atp-binding]]
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[[Category: chaperone]]
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[[Category: Chaperone]]
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[[Category: cytoplasm]]
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[[Category: Cytoplasm]]
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[[Category: nucleotide-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: phosphorylation]]
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[[Category: Phosphorylation]]
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[[Category: stress response]]
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[[Category: Stress response]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:35:55 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:11:03 2008''
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Revision as of 15:35, 4 May 2008

Image:2vcj.jpg

Template:STRUCTURE 2vcj

4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER


Overview

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%.

About this Structure

2VCJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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 Page seeded by OCA on Sun May 4 18:35:55 2008

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