Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800.
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.
Stühmer
Thorsten
T
Department of Internal Medicine II, Division of Haematology, University Hospital Würzburg, Würzburg, Bavaria, Germany. stuehmer_t@medizin.uni-wuerzburg.de
Chatterjee
Manik
M
Grella
Evelyn
E
Seggewiss
Ruth
R
Langer
Christian
C
Müller
Sabine
S
Schoepfer
Joseph
J
Garcia-Echeverria
Carlos
C
Quadt
Cornelia
C
Jensen
Michael R
MR
Einsele
Hermann
H
Bargou
Ralf C
RC
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
D018841:HSP90 Heat-Shock Proteins; C547235:NVP-BEP800; D009363:Neoplasm Proteins; D011743:Pyrimidines