TY - JOUR
T1 - 4,5-diarylisoxazole HSP90 chaperone inhibitors
T2 - potential therapeutic agents for the treatment of cancer
AU - Brough, Paul A.
AU - Aherne, Wynne
AU - Barril, Xavier
AU - Borgognoni, Jenifer
AU - Boxall, Kathy
AU - Cansfield, Julie E.
AU - Cheung, Kwai-Miny J.
AU - Collins, Ian
AU - Davies, Nicholas G. M.
AU - Drysdale, Martin J.
AU - Dymock, Brian
AU - Eccles, Suzanne A.
AU - Finch, Harry
AU - Fink, Alexandra
AU - Hayes, Angela
AU - Howes, Robert
AU - Hubbard, Roderick E.
AU - James, Karen
AU - Jordan, Allan M.
AU - Lockie, Andrea
AU - Martins, Vanessa
AU - Massey, Andrew
AU - Matthews, Thomas P.
AU - McDonald, Edward
AU - Northfield, Christopher J.
AU - Pearl, Laurence H.
AU - Prodromou, Chrisostomos
AU - Ray, Stuart
AU - Raynaud, Florence I.
AU - Roughley, Stephen D.
AU - Sharp, Swee Y.
AU - Surgenor, Allan
AU - Walmsley, D. Lee
AU - Webb, Paul
AU - Wood, Mike
AU - Workman, Paul
AU - Wrightt, Lisa
PY - 2008/1/24
Y1 - 2008/1/24
N2 - 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 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 similar to 50%.
AB - 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 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 similar to 50%.
KW - SHOCK-PROTEIN 90
KW - MOLECULAR CHAPERONE
KW - HEAT-SHOCK-PROTEIN-90 INHIBITORS
KW - IN-VITRO
KW - PHASE-I
KW - SIGNALING PATHWAYS
KW - ANTICANCER AGENT
KW - ATP BINDING
KW - GELDANAMYCIN
KW - 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN
UR - http://www.scopus.com/inward/record.url?scp=38349157746&partnerID=8YFLogxK
U2 - 10.1021/jm701018h
DO - 10.1021/jm701018h
M3 - Article
SN - 0022-2623
VL - 51
SP - 196
EP - 218
JO - JOURNAL OF MEDICINAL CHEMISTRY
JF - JOURNAL OF MEDICINAL CHEMISTRY
IS - 2
ER -