Discovery of XL413, a potent and selective CDC7 inhibitor

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31. doi: 10.1016/j.bmcl.2012.04.024. Epub 2012 Apr 16.

Abstract

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Computer Simulation
  • Humans
  • Mice
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics*
  • Pyrimidinones / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Up-Regulation

Substances

  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • XL413 compound
  • CDC7 protein, human
  • Protein-Serine-Threonine Kinases