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.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. Sue.Eccles@icr.ac.uk
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Andy
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authors.forename: Sharon
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authors.lastname: Gowan
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authors.lastname: Aherne
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authors.forename: Angela
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authors.lastname: Hayes
authors.forename: Vanessa
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authors.lastname: Martins
authors.forename: Frederique
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authors.lastname: Urban
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authors.lastname: Boxall
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence
authors.initials: L
authors.lastname: Pearl
authors.forename: Karen
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authors.lastname: James
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Kwai-Ming
authors.initials: KM
authors.lastname: Cheung
authors.forename: Andrew
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authors.lastname: Kalusa
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brough
authors.forename: Julie E
authors.initials: JE
authors.lastname: Cansfield
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Harry
authors.initials: H
authors.lastname: Finch
authors.forename: Rob
authors.initials: R
authors.lastname: Howes
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
authors.forename: Alan
authors.initials: A
authors.lastname: Surgenor
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Mike
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authors.lastname: Wood
authors.forename: Lisa
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authors.lastname: Wright
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authors.lastname: Workman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012118:Resorcinols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols