The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.
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.
Evans
Robert P
RP
Department of Oncology, University of Alberta/Cross Cancer Institute, Edmonton, AB, Canada.
Naber
Claudia
C
Steffler
Tara
T
Checkland
Tamara
T
Maxwell
Christopher A
CA
Keats
Jonathan J
JJ
Belch
Andrew R
AR
Pilarski
Linda M
LM
Lai
Raymond
R
Reiman
Tony
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010755:Organophosphates / Q000627:therapeutic use*; D010950:Plasma Cells / Q000201:enzymology / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053668:Syndecan-1 / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D011799:Quinazolines; D012333:RNA, Messenger; D053668:Syndecan-1; C576917:AURKA protein, human; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases