Details

Autor(en) / Beteiligte

• Zabludoff, Sonya D
• Deng, Chun
• Grondine, Michael R
• Sheehy, Adam M
• Ashwell, Susan
• Caleb, Benjamin L
• Green, Stephen
• Haye, Heather R
• Horn, Candice L
• Janetka, James W
• Liu, Dongfang
• Mouchet, Elizabeth
• Ready, Shannon
• Rosenthal, Judith L
• Queva, Christophe
• Schwartz, Gary K
• Taylor, Karen J
• Tse, Archie N
• Walker, Graeme E
• White, Anne M

Titel

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

Ist Teil von

• Molecular cancer therapeutics, 2008-09, Vol.7 (9), p.2955-2966

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2008

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 G 1 -DNA damage checkpoint pathway resulting in reliance on S and G 2 checkpoints for DNA repair and cell survival. The S and G 2 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 G 1 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. [Mol Cancer Ther 2008;7(9):2955–66]