title: The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.
abstract: A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.
authors.affiliation: Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Menezes
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Tinya
authors.initials: T
authors.lastname: Abrams
authors.forename: Darrin
authors.initials: D
authors.lastname: Stuart
authors.forename: Guoying Karen
authors.initials: GK
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Duhl
authors.forename: Timothy
authors.initials: T
authors.lastname: Machajewski
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pryer
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
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; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D011728:Pyridones; D011743:Pyrimidines