Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships

J Med Chem. 2008 Feb 14;51(3):487-501. doi: 10.1021/jm700956r. Epub 2008 Jan 18.

Abstract

Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Furans
  • Pyridones
  • Pyrroles
  • CDC7 protein, human
  • Protein-Serine-Threonine Kinases