DNA-dependent protein kinase inhibitors as drug candidates for the treatment of cancer.
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.
Kashishian
Adam
A
ICOS Corporation, Bothell, WA, USA.
Douangpanya
Heather
H
Clark
Darcey
D
Schlachter
Stephen T
ST
Eary
C Todd
CT
Schiro
Justin G
JG
Huang
Hongmei
H
Burgess
Larry E
LE
Kesicki
Edward A
EA
Halbrook
James
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases