This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kashishian, A. Articles by Halbrook, J. Search for Related Content PubMed PubMed Citation Articles by Kashishian, A. Articles by Halbrook, J.

¹ ICOS Corporation, Bothell, WA and ² Array Biopharma, Boulder, CO

Requests for Reprints: James Halbrook, 5812 W. Mercer Way, Mercer Island, WA 98046. Phone: (425) 941-5013; E-mail: jimhalbrook{at}aol.com

Cancer presents a difficult challenge for oncologists, as there are few therapies that specifically target disease cells. Existing treatment strategies rely heavily on physical and chemical agents that nonspecifically affect DNA metabolism. To improve the effectiveness of these treatments, we have identified a new class of protein kinase inhibitor that targets a major DNA repair pathway. A representative of this class, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone, inhibits the DNA-dependent protein kinase (DNA-PK) and differs significantly from previously studied DNA-PK inhibitors both structurally and functionally. DNA-PK participates in the cellular response to and repair of chromosomal DNA double-strand breaks (DSBs). These new selective inhibitors recapitulate the phenotype of DNA-PK defective cell lines including those from SCID mice. These compounds directly inhibit the repair of DNA DSBs and consequently enhance the cytotoxicity of physical and chemical agents that induce DSBs but not other DNA lesions. In contrast to previously studied DNA-PK inhibitors, these compounds appear benign, exhibiting no toxic effects in the absence of DSB-inducing treatments. Most importantly, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone synergistically enhances radiation-induced tumor control in a mouse-human xenograft assay. These studies validate DNA-PK as a cancer drug target and suggest a new approach for enhancing the effects of existing cancer therapies.

Received 5/27/03; revised 8/ 6/03; accepted 9/10/03.

This article has been cited by other articles:

				S. Yotsumoto, K. Saegusa, and Y. Aramaki Endosomal Translocation of CpG-Oligodeoxynucleotides Inhibits DNA-PKcs-Dependent IL-10 Production in Macrophages J. Immunol., January 15, 2008; 180(2): 809 - 816. [Abstract] [Full Text] [PDF]

				L. Amrein, M. Loignon, A.-C. Goulet, M. Dunn, B. Jean-Claude, R. Aloyz, and L. Panasci Chlorambucil Cytotoxicity in Malignant B Lymphocytes Is Synergistically Increased by 2-(Morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-Mediated Inhibition of DNA Double-Strand Break Repair via Inhibition of DNA-Dependent Protein Kinase J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 848 - 855. [Abstract] [Full Text] [PDF]

				V. Rodriguez-Bravo, S. Guaita-Esteruelas, R. Florensa, O. Bachs, and N. Agell Chk1- and Claspin-Dependent but ATR/ATM- and Rad17-Independent DNA Replication Checkpoint Response in HeLa Cells. Cancer Res., September 1, 2006; 66(17): 8672 - 8679. [Abstract] [Full Text] [PDF]

				Y. Zhao, H. D. Thomas, M. A. Batey, I. G. Cowell, C. J. Richardson, R. J. Griffin, A. H. Calvert, D. R. Newell, G. C.M. Smith, and N. J. Curtin Preclinical Evaluation of a Potent Novel DNA-Dependent Protein Kinase Inhibitor NU7441. Cancer Res., May 15, 2006; 66(10): 5354 - 5362. [Abstract] [Full Text] [PDF]

				C. M. Sturgeon, Z. A. Knight, K. M. Shokat, and M. Roberge Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage. Mol. Cancer Ther., April 1, 2006; 5(4): 885 - 892. [Abstract] [Full Text] [PDF]

				E. T. Shinohara, L. Geng, J. Tan, H. Chen, Y. Shir, E. Edwards, J. Halbrook, E. A. Kesicki, A. Kashishian, and D. E. Hallahan DNA-Dependent Protein Kinase Is a Molecular Target for the Development of Noncytotoxic Radiation-Sensitizing Drugs Cancer Res., June 15, 2005; 65(12): 4987 - 4992. [Abstract] [Full Text] [PDF]

				S. M. Bailey, M. A. Brenneman, and E. H. Goodwin Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells Nucleic Acids Res., July 16, 2004; 32(12): 3743 - 3751. [Abstract] [Full Text] [PDF]