title: NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models.
abstract: BACKGROUND
  Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.
  
  
  METHODS
  The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.
  
  
  RESULTS
  We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion--hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.
  
  
  CONCLUSIONS
  NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials.
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland. michael_rugaard.jensen@novartis.com
authors.forename: Michael Rugaard
authors.initials: MR
authors.lastname: Jensen
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.forename: Andrew
authors.initials: A
authors.lastname: Massey
authors.forename: Chantale T
authors.initials: CT
authors.lastname: Guy
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Alan
authors.initials: A
authors.lastname: Buckler
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012118:Resorcinols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018832:Molecular Chaperones; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D012118:Resorcinols; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C524056:Erbb2 protein, mouse