4,5-diarylisoxazole HSP90 chaperone inhibitors:  potential therapeutic agents for the treatment of cancer

Paul A. Brough; Wynne Aherne; Xavier Barril; Jenifer Borgognoni; Kathy Boxall; Julie E. Cansfield; Kwai-Miny J. Cheung; Ian Collins; Nicholas G. M. Davies; Martin J. Drysdale; Brian Dymock; Suzanne A. Eccles; Harry Finch; Alexandra Fink; Angela Hayes; Robert Howes; Roderick E. Hubbard; Karen James; Allan M. Jordan; Andrea Lockie; Vanessa Martins; Andrew Massey; Thomas P. Matthews; Edward McDonald; Christopher J. Northfield; Laurence H. Pearl; Chrisostomos Prodromou; Stuart Ray; Florence I. Raynaud; Stephen D. Roughley; Swee Y. Sharp; Allan Surgenor; D. Lee Walmsley; Paul Webb; Mike Wood; Paul Workman; Lisa Wrightt

doi:10.1021/jm701018h

4,5-diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

Paul A. Brough, Wynne Aherne, Xavier Barril, Jenifer Borgognoni, Kathy Boxall, Julie E. Cansfield, Kwai-Miny J. Cheung, Ian Collins, Nicholas G. M. Davies, Martin J. Drysdale, Brian Dymock, Suzanne A. Eccles, Harry Finch, Alexandra Fink, Angela Hayes, Robert Howes, Roderick E. Hubbard, Karen James, Allan M. Jordan, Andrea LockieVanessa Martins, Andrew Massey, Thomas P. Matthews, Edward McDonald, Christopher J. Northfield, Laurence H. Pearl, Chrisostomos Prodromou, Stuart Ray, Florence I. Raynaud, Stephen D. Roughley, Swee Y. Sharp, Allan Surgenor, D. Lee Walmsley, Paul Webb, Mike Wood, Paul Workman, Lisa Wrightt

Chemistry

Research output: Contribution to journal › Article › peer-review

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 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%.

Original language	English
Pages (from-to)	196-218
Number of pages	23
Journal	JOURNAL OF MEDICINAL CHEMISTRY
Volume	51
Issue number	2
DOIs	https://doi.org/10.1021/jm701018h
Publication status	Published - 24 Jan 2008

Keywords

SHOCK-PROTEIN 90
MOLECULAR CHAPERONE
HEAT-SHOCK-PROTEIN-90 INHIBITORS
IN-VITRO
PHASE-I
SIGNALING PATHWAYS
ANTICANCER AGENT
ATP BINDING
GELDANAMYCIN
17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN

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10.1021/jm701018h

http://pubs.acs.org/doi/abs/10.1021/jm701018h

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Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., 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., ... Wrightt, L. (2008). 4,5-diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. JOURNAL OF MEDICINAL CHEMISTRY, 51(2), 196-218. https://doi.org/10.1021/jm701018h

@article{658e07611a81481d958403858c291abb,

title = "4,5-diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer",

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 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%.",

keywords = "SHOCK-PROTEIN 90, MOLECULAR CHAPERONE, HEAT-SHOCK-PROTEIN-90 INHIBITORS, IN-VITRO, PHASE-I, SIGNALING PATHWAYS, ANTICANCER AGENT, ATP BINDING, GELDANAMYCIN, 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN",

author = "Brough, {Paul A.} and Wynne Aherne and Xavier Barril and Jenifer Borgognoni and Kathy Boxall and Cansfield, {Julie E.} and Cheung, {Kwai-Miny J.} and Ian Collins and Davies, {Nicholas G. M.} and Drysdale, {Martin J.} and Brian Dymock and Eccles, {Suzanne A.} and Harry Finch and Alexandra Fink and Angela Hayes and Robert Howes and Hubbard, {Roderick E.} and Karen James and Jordan, {Allan M.} and Andrea Lockie and Vanessa Martins and Andrew Massey and Matthews, {Thomas P.} and Edward McDonald and Northfield, {Christopher J.} and Pearl, {Laurence H.} and Chrisostomos Prodromou and Stuart Ray and Raynaud, {Florence I.} and Roughley, {Stephen D.} and Sharp, {Swee Y.} and Allan Surgenor and Walmsley, {D. Lee} and Paul Webb and Mike Wood and Paul Workman and Lisa Wrightt",

year = "2008",

month = jan,

day = "24",

doi = "10.1021/jm701018h",

language = "English",

volume = "51",

pages = "196--218",

journal = "JOURNAL OF MEDICINAL CHEMISTRY",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

}

Brough, PA, Aherne, W, Barril, X, Borgognoni, J, Boxall, K, Cansfield, JE, Cheung, K-MJ, Collins, I, Davies, NGM, 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 & Wrightt, L 2008, '4,5-diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer', JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 2, pp. 196-218. https://doi.org/10.1021/jm701018h

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 -

4,5-diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

Abstract

Keywords

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