title: Preclinical activity of the novel orally bioavailable HSP90 inhibitor NVP-HSP990 against multiple myeloma cells.
abstract: BACKGROUND
  HSP90 inhibitors effectively reduce expression and activity levels of oncogenic survival proteins. However, their clinical anti-multiple myeloma (MM) activity has been found to be rather weak, spurring the exploration of combination therapies and development of compounds with improved physicochemical properties.
  
  
  METHODS
  Preclinical effects of the novel orally bioavailable HSP90 inhibitor NVP-HSP990 on the viability, apoptosis and client protein levels of MM cells (established cell lines and clinical specimens) were tested alone and in combination with other drugs.
  
  
  RESULTS
  NVP-HSP990 exerted profound activity against MM cells, with a molecular mode of action conforming well with its role as HSP90 inhibitor. Enhanced activity was most obvious in combination with melphalan. Combination with a phosphatidylinositol-3-kinase (PI3-kinase)/mammalian target of rapamycin (mTOR) inhibitor, rendered the HSP90 blockade-mediated stress response ineffective and considerably increased the anti-MM toxicity.
  
  
  CONCLUSIONS
  Given the current interest in both HSP90 and PI3-kinase/mTOR as potential clinical targets, these observations could broaden the therapeutic utility of either class of inhibitor in MM.
authors.affiliation: Department of Internal Medicine II, Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany. stuehmer_t@medizin.uni-wuerzburg.de
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Kamol
authors.initials: K
authors.lastname: Iskandarov
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Gao
authors.forename: Thomas
authors.initials: T
authors.lastname: Bumm
authors.forename: Evelyn
authors.initials: E
authors.lastname: Grella
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; D005663:Furans; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines