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The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.

Abstract
Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.
AuthorsRobert P Evans, Claudia Naber, Tara Steffler, Tamara Checkland, Christopher A Maxwell, Jonathan J Keats, Andrew R Belch, Linda M Pilarski, Raymond Lai, Tony Reiman
JournalBritish journal of haematology (Br J Haematol) Vol. 140 Issue 3 Pg. 295-302 (Feb 2008) ISSN: 1365-2141 [Electronic] England
PMID18076711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • Antineoplastic Agents
  • Organophosphates
  • Quinazolines
  • RNA, Messenger
  • Syndecan-1
  • AURKA protein, human
  • AURKB protein, human
  • Aurka protein, mouse
  • Aurkb protein, mouse
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
Topics
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Apoptosis
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Line, Tumor
  • Flow Cytometry
  • Humans
  • Immunophenotyping
  • Mice
  • Mice, SCID
  • Multiple Myeloma (drug therapy, enzymology, pathology)
  • Organophosphates (therapeutic use)
  • Plasma Cells (enzymology, immunology)
  • Protein Serine-Threonine Kinases (analysis, antagonists & inhibitors, genetics)
  • Quinazolines (therapeutic use)
  • RNA, Messenger (analysis)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Syndecan-1 (analysis)
  • Xenograft Model Antitumor Assays

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