NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis

Suzanne A. Eccles; Andy Massey; Florence I. Raynaud; Swee Y. Sharp; Gary Box; Melanie Valenti; Lisa Patterson; Alexis de Haven Brandon; Sharon Gowan; Frances Boxall; Wynne Aherne; Martin Rowlands; Angela Hayes; Vanessa Martins; Frederique Urban; Kathy Boxall; Chrisostomos Prodromou; Laurence Pearl; Karen James; Thomas P. Matthews; Kwai-Ming Cheung; Andrew Kalusa; Keith Jones; Edward McDonald; Xavier Barril; Paul A. Brough; Julie E. Cansfield; Brian Dymock; Martin J. Drysdale; Harry Finch; Rob Howes; Roderick E. Hubbard; Alan Surgenor; Paul Webb; Mike Wood; Lisa Wright; Paul Workman

doi:10.1158/0008-5472.CAN-07-5256

NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis

Suzanne A. Eccles, Andy Massey, Florence I. Raynaud, Swee Y. Sharp, Gary Box, Melanie Valenti, Lisa Patterson, Alexis de Haven Brandon, Sharon Gowan, Frances Boxall, Wynne Aherne, Martin Rowlands, Angela Hayes, Vanessa Martins, Frederique Urban, Kathy Boxall, Chrisostomos Prodromou, Laurence Pearl, Karen James, Thomas P. MatthewsKwai-Ming Cheung, Andrew Kalusa, Keith Jones, Edward McDonald, Xavier Barril, Paul A. Brough, Julie E. Cansfield, Brian Dymock, Martin J. Drysdale, Harry Finch, Rob Howes, Roderick E. Hubbard, Alan Surgenor, Paul Webb, Mike Wood, Lisa Wright, Paul Workman

Chemistry

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

Abstract

We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.

Original language	English
Pages (from-to)	2850-2860
Number of pages	11
Journal	Cancer research
Volume	68
Issue number	8
DOIs	https://doi.org/10.1158/0008-5472.CAN-07-5256
Publication status	Published - 15 Apr 2008

Keywords

HSP90 MOLECULAR CHAPERONE
SHOCK-PROTEIN 90
IN-VITRO
BREAST-CANCER
DT-DIAPHORASE
B-RAF
17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN
EXPRESSION
POTENT
CELLS

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10.1158/0008-5472.CAN-07-5256

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Eccles, S. A., Massey, A., Raynaud, F. I., Sharp, S. Y., Box, G., Valenti, M., Patterson, L., Brandon, A. D. H., Gowan, S., Boxall, F., Aherne, W., Rowlands, M., Hayes, A., Martins, V., Urban, F., Boxall, K., Prodromou, C., Pearl, L., James, K., ... Workman, P. (2008). NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer research, 68(8), 2850-2860. https://doi.org/10.1158/0008-5472.CAN-07-5256

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title = "NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis",

abstract = "We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.",

keywords = "HSP90 MOLECULAR CHAPERONE, SHOCK-PROTEIN 90, IN-VITRO, BREAST-CANCER, DT-DIAPHORASE, B-RAF, 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN, EXPRESSION, POTENT, CELLS",

author = "Eccles, {Suzanne A.} and Andy Massey and Raynaud, {Florence I.} and Sharp, {Swee Y.} and Gary Box and Melanie Valenti and Lisa Patterson and Brandon, {Alexis de Haven} and Sharon Gowan and Frances Boxall and Wynne Aherne and Martin Rowlands and Angela Hayes and Vanessa Martins and Frederique Urban and Kathy Boxall and Chrisostomos Prodromou and Laurence Pearl and Karen James and Matthews, {Thomas P.} and Kwai-Ming Cheung and Andrew Kalusa and Keith Jones and Edward McDonald and Xavier Barril and Brough, {Paul A.} and Cansfield, {Julie E.} and Brian Dymock and Drysdale, {Martin J.} and Harry Finch and Rob Howes and Hubbard, {Roderick E.} and Alan Surgenor and Paul Webb and Mike Wood and Lisa Wright and Paul Workman",

year = "2008",

month = apr,

day = "15",

doi = "10.1158/0008-5472.CAN-07-5256",

language = "English",

volume = "68",

pages = "2850--2860",

journal = "Cancer research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "8",

}

Eccles, SA, Massey, A, Raynaud, FI, Sharp, SY, Box, G, Valenti, M, Patterson, L, Brandon, ADH, Gowan, S, Boxall, F, Aherne, W, Rowlands, M, Hayes, A, Martins, V, Urban, F, Boxall, K, Prodromou, C, Pearl, L, James, K, Matthews, TP, Cheung, K-M, Kalusa, A, Jones, K, McDonald, E, Barril, X, Brough, PA, Cansfield, JE, Dymock, B, Drysdale, MJ, Finch, H, Howes, R, Hubbard, RE, Surgenor, A, Webb, P, Wood, M, Wright, L & Workman, P 2008, 'NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis', Cancer research, vol. 68, no. 8, pp. 2850-2860. https://doi.org/10.1158/0008-5472.CAN-07-5256

TY - JOUR

T1 - NVP-AUY922

T2 - a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis

AU - Eccles, Suzanne A.

AU - Massey, Andy

AU - Raynaud, Florence I.

AU - Sharp, Swee Y.

AU - Box, Gary

AU - Valenti, Melanie

AU - Patterson, Lisa

AU - Brandon, Alexis de Haven

AU - Gowan, Sharon

AU - Boxall, Frances

AU - Aherne, Wynne

AU - Rowlands, Martin

AU - Hayes, Angela

AU - Martins, Vanessa

AU - Urban, Frederique

AU - Boxall, Kathy

AU - Prodromou, Chrisostomos

AU - Pearl, Laurence

AU - James, Karen

AU - Matthews, Thomas P.

AU - Cheung, Kwai-Ming

AU - Kalusa, Andrew

AU - Jones, Keith

AU - McDonald, Edward

AU - Barril, Xavier

AU - Brough, Paul A.

AU - Cansfield, Julie E.

AU - Dymock, Brian

AU - Drysdale, Martin J.

AU - Finch, Harry

AU - Howes, Rob

AU - Hubbard, Roderick E.

AU - Surgenor, Alan

AU - Webb, Paul

AU - Wood, Mike

AU - Wright, Lisa

AU - Workman, Paul

PY - 2008/4/15

Y1 - 2008/4/15

N2 - We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.

AB - We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.

KW - HSP90 MOLECULAR CHAPERONE

KW - SHOCK-PROTEIN 90

KW - IN-VITRO

KW - BREAST-CANCER

KW - DT-DIAPHORASE

KW - B-RAF

KW - 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN

KW - EXPRESSION

KW - POTENT

KW - CELLS

UR - http://www.scopus.com/inward/record.url?scp=42349084306&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-5256

DO - 10.1158/0008-5472.CAN-07-5256

M3 - Article

C2 - 18413753

SN - 0008-5472

VL - 68

SP - 2850

EP - 2860

JO - Cancer research

JF - Cancer research

IS - 8

ER -

NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis

Abstract

Keywords

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