Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles

Mol Cancer Ther. 2017 Jun;16(6):1031-1040. doi: 10.1158/1535-7163.MCT-16-0580. Epub 2017 Mar 14.


Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031-40. ©2017 AACR.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Apoptosis / drug effects
  • Aurora Kinase B / antagonists & inhibitors*
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Line, Tumor
  • Cytarabine / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology*
  • Mice
  • Nanoparticles*
  • Organophosphates / administration & dosage*
  • Organophosphates / pharmacokinetics
  • Polyploidy
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Quinazolines / administration & dosage*
  • Quinazolines / pharmacokinetics
  • Rats
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • 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
  • Protein Kinase Inhibitors
  • Quinazolines
  • Cytarabine
  • Aurora Kinase B