2vci: Difference between revisions
New page: left|200px<br /><applet load="2vci" size="350" color="white" frame="true" align="right" spinBox="true" caption="2vci, resolution 2.00Å" /> '''4,5 DIARYL ISOXAZOLE... |
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caption="2vci, resolution 2.00Å" /> | caption="2vci, resolution 2.00Å" /> | ||
'''4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER'''<br /> | '''4,5 DIARYL ISOXAZOLE HSP90 CHAPERONE INHIBITORS: POTENTIAL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER'''<br /> | ||
==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 (IC 50 = 21, nM) and inhibits proliferation of various human cancer cell lines in, vitro, with GI 50 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== | ==About this Structure== | ||
2VCI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=2GJ:'>2GJ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Site: <scene name='pdbsite=AC1:2gj Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VCI OCA]. | 2VCI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=2GJ:'>2GJ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Site: <scene name='pdbsite=AC1:2gj Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VCI 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18020435 18020435] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: Martins, V.]] | [[Category: Martins, V.]] | ||
[[Category: Massey, A.]] | [[Category: Massey, A.]] | ||
[[Category: Matthews, T.]] | [[Category: Matthews, T.P.]] | ||
[[Category: Mcdonald, E.]] | [[Category: Mcdonald, E.]] | ||
[[Category: Northfield, C.J.]] | [[Category: Northfield, C.J.]] | ||
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[[Category: stress response]] | [[Category: stress response]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jan 31 11:00:59 2008'' | ||
