2vci: Difference between revisions

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%.

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].  

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: Brough, P A.]]

[[Category: Cansfield, J E.]]

[[Category: Cheung, K M.]]

[[Category: Davies, N G.M.]]

[[Category: Drysdale, M J.]]

[[Category: Eccles, S A.]]

[[Category: Hubbard, R E.]]

[[Category: Jordan, A M.]]

[[Category: Matthews, T P.]]

[[Category: Northfield, C J.]]

[[Category: Pearl, L H.]]

[[Category: Raynaud, F I.]]

[[Category: Roughley, S D.]]

[[Category: Sharp, S Y.]]

[[Category: Walmsley, D L.]]

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