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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 8 Pg. 2850-60 (Apr 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18413753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Resorcinols

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacokinetics, therapeutic use)
• Mice
• Mice, Nude
• Neoplasm Metastasis (prevention & control)
• Neovascularization, Pathologic (prevention & control)
• Resorcinols (pharmacokinetics, therapeutic use)
• Transplantation, Heterologous