The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis
Open accessAbstract
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 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 GI50. 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-1α, 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. [Cancer Res 2008;68(8):2850–60]
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Cites
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502
Roe, S. M., Prodromou, C., O'Brien, R., Ladbury, J. E., Piper, P. W., & Pearl, L. H. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm980403y · Cited by 1,004
Self-citationHsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663
Cited by
Insulin and insulin-like growth factor signalling in neoplasia
Pollak, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2536 · Cited by 2,059
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Apoptosis and Molecular Targeting Therapy in Cancer
Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y., & Sakuragi, N. (2014) · BioMed Research International · doi:10.1155/2014/150845 · Cited by 1,121
RetractedCombinatorial drug therapy for cancer in the post-genomic era
Al-Lazikani, B., Banerji, U., & Workman, P. (2012) · Nature Biotechnology · doi:10.1038/nbt.2284 · Cited by 1,070
Self-citationDiscovery of drug mode of action and drug repositioning from transcriptional responses
Iorio, F., Bosotti, R., Scacheri, E., Belcastro, V., Mithbaokar, P., Ferriero, R., Murino, L., Tagliaferri, R., Brunetti-Pierri, N., Isacchi, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000138107 · Cited by 816
Metadata
- Authors
- Eccles, S. A., Massey, A., Raynaud, F. I., Sharp, S. Y., Box, G., Valenti, M., Patterson, L., de Haven Brandon, A., Gowan, S., Boxall, F., Aherne, W., Rowlands, M., Hayes, A., Martins, V., Urban, F., Boxall, K., Prodromou, C., Pearl, L., James, K., Matthews, T. P., Cheung, K.-M., Kalusa, A., Jones, K., McDonald, E., Barril, X., Brough, P. A., Cansfield, J. E., Dymock, B., Drysdale, M. J., Finch, H., Howes, R., Hubbard, R. E., Surgenor, A., Webb, P., Wood, M., Wright, L., & Workman, P.
- Venue
- Cancer Research
- Published
- 2008-04-15
- Volume
- 68
- Issue
- 8
- Pages
- 2850-2860
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2166999544
- Cited by
- 479
- References
- 4
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- green
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- Eccles, S. A., Massey, A., Raynaud, F. I., Sharp, S. Y., Box, G., Valenti, M., Patterson, L., de Haven Brandon, A., 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. https://doi.org/10.1158/0008-5472.can-07-5256
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