AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies

Mol Cancer Ther. 2008 Sep;7(9):2955-66. doi: 10.1158/1535-7163.MCT-08-0492.

Abstract

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.

MeSH terms

  • Animals
  • Biological Assay
  • Cell Cycle Proteins / metabolism
  • Cell Death / drug effects
  • Checkpoint Kinase 1
  • DNA Damage*
  • DNA, Neoplasm / metabolism*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • G2 Phase / drug effects
  • Gemcitabine
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice
  • Mutation / genetics
  • Protein Kinase Inhibitors / analysis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Rats
  • Thiophenes / analysis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Topotecan / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • Urea / analogs & derivatives*
  • Urea / analysis
  • Urea / chemistry
  • Urea / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
  • Cell Cycle Proteins
  • DNA, Neoplasm
  • Protein Kinase Inhibitors
  • Thiophenes
  • Tumor Suppressor Protein p53
  • Deoxycytidine
  • Topotecan
  • Urea
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek1 protein, rat
  • Gemcitabine