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-Ming 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 Wright

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-Ming 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 Wright

Cancer Research UK Manchester Institute

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 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%.

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

Keywords

Animals
Antineoplastic Agents
Binding, Competitive
Cell Line, Tumor
Cell Proliferation
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Fluorescence Polarization
HSP90 Heat-Shock Proteins
Humans
Isoxazoles
Mice
Mice, Nude
Models, Molecular
Neoplasm Transplantation
Resorcinols
Structure-Activity Relationship
Transplantation, Heterologous

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., ... Wright, L. (2008). 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem, 51(2), 196-218. https://doi.org/10.1021/jm701018h

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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 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%.",

keywords = "Animals, Antineoplastic Agents, Binding, Competitive, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Fluorescence Polarization, HSP90 Heat-Shock Proteins, Humans, Isoxazoles, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Resorcinols, Structure-Activity Relationship, Transplantation, Heterologous",

author = "Brough, {Paul A} and Wynne Aherne and Xavier Barril and Jenifer Borgognoni and Kathy Boxall and Cansfield, {Julie E} and Cheung, {Kwai-Ming 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 Wright",

year = "2008",

month = jan,

day = "24",

doi = "10.1021/jm701018h",

language = "English",

volume = "51",

pages = "196--218",

journal = "J Med Chem",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

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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 & Wright, L 2008, '4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer', J Med Chem, 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-Ming 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 - Wright, 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 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%.

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 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%.

KW - Animals

KW - Antineoplastic Agents

KW - Binding, Competitive

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Crystallography, X-Ray

KW - Drug Screening Assays, Antitumor

KW - Fluorescence Polarization

KW - HSP90 Heat-Shock Proteins

KW - Humans

KW - Isoxazoles

KW - Mice

KW - Mice, Nude

KW - Models, Molecular

KW - Neoplasm Transplantation

KW - Resorcinols

KW - Structure-Activity Relationship

KW - Transplantation, Heterologous

U2 - 10.1021/jm701018h

DO - 10.1021/jm701018h

M3 - Article

C2 - 18020435

SN - 0022-2623

VL - 51

SP - 196

EP - 218

JO - J Med Chem

JF - J Med Chem

IS - 2

ER -

4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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