Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase

J Med Chem. 2007 May 3;50(9):2213-24. doi: 10.1021/jm061335f. Epub 2007 Mar 21.

Abstract

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Screening Assays, Antitumor
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / drug effects
  • Female
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Organophosphates / chemical synthesis*
  • Organophosphates / pharmacokinetics
  • Organophosphates / pharmacology
  • Phosphorylation
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • 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
  • Cytochrome P-450 Enzyme Inhibitors
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Histones
  • Organophosphates
  • Prodrugs
  • Pyrazoles
  • Quinazolines
  • Recombinant Proteins
  • AURKB protein, human
  • Aurka protein, mouse
  • Aurka protein, rat
  • Aurkb protein, mouse
  • Aurkb protein, rat
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases