title: Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.
abstract: Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH(2)-terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf(V600E), Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development. Mol Cancer Ther; 9(4); 906-19. (c)2010 AACR.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Klybeckstrasse 141, WKL-125.2.42, CH-4057 Basel, Switzerland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brough
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pfaar
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.forename: Alain
authors.initials: A
authors.lastname: Schweitzer
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Michael Rugaard
authors.initials: MR
authors.lastname: Jensen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; C547235:NVP-BEP800; D011743:Pyrimidines; D012118:Resorcinols