AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies Journal Article
| Authors: | Zabludoff, S. D.; Deng, C.; Grondine, M. R.; Sheehy, A. M.; Ashwell, S.; Caleb, B. L.; Green, S.; Haye, H. R.; Horn, C. L.; Janetka, J. W.; Liu, D.; Mouchet, E.; Ready, S.; Rosenthal, J. L.; Queva, C.; Schwartz, G. K.; Taylor, K. J.; Tse, A. N.; Walker, G. E.; White, A. M. |
| Article Title: | AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies |
| 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. Copyright © 2008 American Association for Cancer Research. |
| Keywords: | cancer chemotherapy; unclassified drug; mutation; dose response; nonhuman; gemcitabine; cancer radiotherapy; topotecan; mouse; animals; cell cycle proteins; mice; cell death; dna damage; low drug dose; protein kinases; animal experiment; 7 ethyl 10 hydroxycamptothecin; hct116 cells; in vivo study; antineoplastic activity; in vitro study; xenograft model antitumor assays; irinotecan; drug synergism; protein kinase inhibitors; xenograft; dna, neoplasm; tumor suppressor protein p53; cell cycle arrest; rats; biological assay; deoxycytidine; ht29 cells; phosphotransferase inhibitor; g2 phase; urea; azd 7762; thiophenes; 3 (carbamoylamino) 5 (3 fluorophenyl) n [3 piperidyl]thiophene 2 carboxamide |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 7 |
| Issue: | 9 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-01-01 |
| Start Page: | 2955 |
| End Page: | 2966 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-08-0492 |
| PUBMED: | 18790776 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 68" - "Export Date: 17 November 2011" - "CODEN: MCTOC" - "Source: Scopus" |
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