2VCJ

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

Summary for 2VCJ

• Entry DOI: 10.2210/pdb2vcj/pdb
• Related: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYI 1UYK 1UYL 1YC1 1YC3 1YC4 2BSM 2BT0 2BUG 2BYH 2BYI 2BZ5 2C2L 2CCS 2CCT 2CCU 2CDD 2UWD 2VCI
• Descriptor: HEAT SHOCK PROTEIN HSP 90-ALPHA, 5-(5-chloro-2,4-dihydroxyphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide (3 entities in total)
• Functional Keywords: alternative splicing, atp-binding, phosphorylation, cytoplasm, chaperone, stress response, nucleotide-binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus : P07900
• Total number of polymer chains: 1
• Total formula weight: 27059.68

Authors

Brough, P.A.,Aherne, W.,Barril, X.,Borgognoni, J.,Boxal, K.,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. (deposition date: 2007-09-24, release date: 2007-12-11, Last modification date: 2023-12-13)

Primary citation

Brough, P.A.,Aherne, W.,Barril, X.,Borgognoni, J.,Boxall, K.,Cansfield, J.E.,Cheung, K.M.,Collins, I.,Davies, N.G.,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.
4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.
J. Med. Chem., 51:196-218, 2008

PubMed Abstract: 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%.

PubMed: 18020435
DOI: 10.1021/jm701018h

Experimental method

X-RAY DIFFRACTION (2.5 Å)