title: Discovery of DNA repair inhibitors by combinatorial library profiling.
abstract: Small molecule inhibitors of DNA repair are emerging as potent and selective anticancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and noncompetitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizes BRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy.
authors.affiliation: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Moeller
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D020552:Comet Assay; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D019151:Peptide Library
chemical_list: D019151:Peptide Library; D051747:DNA-Activated Protein Kinase; D045643:DNA Repair Enzymes