title: The peptide-semicarbazone S-2209, a representative of a new class of proteasome inhibitors, induces apoptosis and cell growth arrest in multiple myeloma cells.
abstract: Bortezomib is the first approved member of a new class of anti-myeloma agents, the proteasome inhibitors. Further proteasome inhibitors are needed to optimise this promising treatment option. S-2209 [1-[1-{1-[(2,4-Dioxo-imidazolidin-1-ylimino)-methyl]-2-phenyl-ethylcarbamoyl}-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(1H-indol)] inhibits the chymotryptic activity of the human 20S proteasome (half maximal effective concentration, IC(50) approximately 220 nmol/l) which was determined by a proteasome inhibition assay. A nuclear factor kappaB inhibition assay revealed a half maximal effective concentration (EC(50)) of 0.9 micromol/l. The WST-1 growth assay showed inhibition of cell growth of all tested multiple myeloma (MM) cell lines with an IC(50) between 100 nmol/l and 600 nmol/l. Strong induction of apoptosis was seen in MM cells at nanomolar concentrations (IC(50) approximately 300 nm) as well as in primary myeloma cells. No induction of apoptosis was detected in peripheral blood mononuclear cells from healthy humans. Upregulation of p53, activation of JNK protein, and downregulation of Mcl-1 was revealed. Despite the administration of 15 mg S-2209/kg/d in wistar rats, no toxicity with respect to body weight, hepatic enzymes, creatinine or haemoglobin was seen. Proteasome inhibition in white blood cells isolated from the treated rats was higher in the S-2209 treated animals in comparison with the control animals treated with 0.1 mg/kg/d bortezomib. S-2209 is active in myeloma cells and shows a favourable toxicity profile in first in-vivo studies. S-2209 is a promising agent for further clinical development.
authors.affiliation: Department of Haematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Munich, Germany. philipp.baumann@med.uni-muenchen.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Baumann
authors.forename: Karin
authors.initials: K
authors.lastname: Müller
authors.forename: Sonja
authors.initials: S
authors.lastname: Mandl-Weber
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.forename: Robert
authors.initials: R
authors.lastname: Doblhofer
authors.forename: Astrid
authors.initials: A
authors.lastname: Ammendola
authors.forename: Roland
authors.initials: R
authors.lastname: Baumgartner
authors.forename: Fuat
authors.initials: F
authors.lastname: Oduncu
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidmaier
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012664:Semicarbazones / Q000494:pharmacology / Q000627:therapeutic use*; D018675:Toxicity Tests; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C540793:(1-(1-((2,4-dioxoimidazolidin-1-ylimino)methyl)-2-phenylethylcarbamoyl)-2-(1H-indol-3-yl)ethylcarbamoyl)-2-(1H-indole); D000963:Antimetabolites; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D010455:Peptides; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012664:Semicarbazones; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D048670:MAP Kinase Kinase 4; D008558:Melphalan