Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Cell Chem Biol. 2017 Sep 21;24(9):1101-1119. doi: 10.1016/j.chembiol.2017.08.027.


To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.

Keywords: BLM DNA helicase; BRCA1; BRCA2; DNA repair; MRE11; PARP inhibitors; PARP1 (poly(ADP-ribose)polymerase1); RAD51; RAD52; RECQ1 DNA helicase; TOP1; WRN DNA helicase; homologous recombination.

Publication types

  • Review

MeSH terms

  • DNA Helicases / antagonists & inhibitors
  • DNA Helicases / metabolism
  • DNA Repair* / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Humans
  • MRE11 Homologue Protein
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Rad51 Recombinase / antagonists & inhibitors
  • Rad51 Recombinase / metabolism
  • Rad52 DNA Repair and Recombination Protein / antagonists & inhibitors
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use


  • DNA-Binding Proteins
  • MRE11 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Rad52 DNA Repair and Recombination Protein
  • Small Molecule Libraries
  • Rad51 Recombinase
  • MRE11 Homologue Protein
  • DNA Helicases