Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition

J Med Chem. 2005 Apr 21;48(8):3080-4. doi: 10.1021/jm049076m.

Abstract

Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aurora Kinases
  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Combinatorial Chemistry Techniques
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • N-(2,6-diethylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzoylamino)-4,6-dihydro-1H-pyrrolo(3,4-c)pyrazole-5-carboxamide
  • Piperazines
  • Pyrroles
  • Adenosine Triphosphate
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases