title: Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800.
abstract: The 90 kD heat shock protein (Hsp90) molecular chaperone sustains multiple components of oncogenic pathways and has recently emerged as a therapeutic target that is now being clinically tested in a number of malignancies. In order to address formulation issues and to deal with possible resistance mechanisms against small molecule Hsp90 inhibitors, a range of compounds based on different molecular scaffolds are now being developed. The present study preclinically tested the effects of the novel 2-aminothienopyrimidine class Hsp90 inhibitor NVP-BEP800, which is suitable for oral formulations, on multiple myeloma cells from established cell lines and on a larger cohort (n = 40) of primary myeloma samples. The drug effectively and specifically killed the majority of primary myeloma cells in coculture with bone marrow stromal cells and reliably entailed molecular consequences of Hsp90 blockade - such as survival pathway breakdown and client protein depletion - in multiple myeloma cells from cell lines as well as from patients. Collectively, the properties of this novel drug support clinical testing in multiple myeloma.
authors.affiliation: Department of Internal Medicine II, Division of Haematology, University Hospital Würzburg, Würzburg, Bavaria, Germany. stuehmer_t@medizin.uni-wuerzburg.de
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Evelyn
authors.initials: E
authors.lastname: Grella
authors.forename: Ruth
authors.initials: R
authors.lastname: Seggewiss
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017154:Stromal Cells / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D018841:HSP90 Heat-Shock Proteins; C547235:NVP-BEP800; D009363:Neoplasm Proteins; D011743:Pyrimidines