Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

Eur J Med Chem. 2014 Jun 10:80:364-82. doi: 10.1016/j.ejmech.2014.04.013. Epub 2014 Apr 5.

Abstract

The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.

Keywords: Cdc7; DNA replication; Kinase inhibitor; MCM2; Thiazole.

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Female
  • HCT116 Cells
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Minichromosome Maintenance Complex Component 2 / metabolism
  • Molecular Docking Simulation
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Thiazoles
  • CDC7 protein, human
  • Protein Serine-Threonine Kinases
  • MCM2 protein, human
  • Minichromosome Maintenance Complex Component 2