title: SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization.
abstract: Loss of the DNA-dependent protein kinase (DNA-PK) results in increased sensitivity to ionizing radiation due to inefficient repair of DNA double-strand breaks. Overexpression of DNA-PK in tumor cells conversely results in resistance to ionizing radiation. It is therefore possible that inhibition of DNA-PK will enhance the preferential killing of tumor cells by radiotherapy. Available inhibitors of DNA-PK, like wortmannin, are cytotoxic and stop the cell cycle because they inhibit phoshatidylinositol-3-kinases at 100-fold lower concentrations required to inhibit DNA-PK. In an effort to develop a specific DNA-PK inhibitor, we have characterized SU11752, from a three-substituted indolin-2-ones library. SU11752 and wortmannin were equally potent inhibitors of DNA-PK. In contrast, inhibition of the phoshatidylinositol-3-kinase p110gamma required 500-fold higher concentration of SU11752. Thus, SU11752 was a more selective inhibitor of DNA-PK than wortmannin. Inhibition kinetics and a direct assay for ATP binding showed that SU11752 inhibited DNA-PK by competing with ATP. SU11752 inhibited DNA double-strand break repair in cells and gave rise to a five-fold sensitization to ionizing radiation. At concentrations of SU11752 that inhibited DNA repair, cell cycle progression was still normal and ATM kinase activity was not inhibited. We conclude that SU11752 defines a new class of drugs that may serve as a starting point for the development of specific DNA-PK inhibitors.
authors.affiliation: Department of Clinical Chemistry, Göteborg University, Sahlgrenska University Hospital, Göteborg 41345, Sweden.
authors.forename: Ismail Hassan
authors.initials: IH
authors.lastname: Ismail
authors.forename: Susanne
authors.initials: S
authors.lastname: Mårtensson
authors.forename: Deborah
authors.initials: D
authors.lastname: Moshinsky
authors.forename: Audie
authors.initials: A
authors.lastname: Rice
authors.forename: Cho
authors.initials: C
authors.lastname: Tang
authors.forename: Anthony
authors.initials: A
authors.lastname: Howlett
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
authors.forename: Ola
authors.initials: O
authors.lastname: Hammarsten
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011839:Radiation, Ionizing
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; C482098:SU11752; D000255:Adenosine Triphosphate; D004247:DNA; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases