Discovery of highly potent and selective pan-Aurora kinase inhibitors with enhanced in vivo antitumor therapeutic index

J Med Chem. 2012 Apr 12;55(7):3250-60. doi: 10.1021/jm201702g. Epub 2012 Mar 14.


Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.

MeSH terms

  • Acetanilides / chemical synthesis*
  • Acetanilides / pharmacokinetics
  • Acetanilides / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A
  • Aurora Kinases
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Histones / metabolism
  • Humans
  • Models, Molecular
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Rats, Nude
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Triazines / chemical synthesis*
  • Triazines / pharmacokinetics
  • Triazines / pharmacology


  • 2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo(2,1-f)(1,2,4)triazin-2-yl)thio)phenyl)acetamide
  • Acetanilides
  • Antineoplastic Agents
  • Histones
  • N-cyclopentyl-1-(2-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo(2,1-f)(1,2,4)triazin-2-yl)thio)phenyl)amino)-2-oxoethyl)pyrrolidine-3-carboxamide
  • Triazines
  • Aurka protein, rat
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases