Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Cell Chem Biol. 2016 Oct 20;23(10):1251-1260. doi: 10.1016/j.chembiol.2016.08.012. Epub 2016 Sep 22.


Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.

Keywords: ADP-ribosylation; ARTD100; DNA repair; PARP10; chemical probe; inhibitor.

MeSH terms

  • ADP Ribose Transferases / antagonists & inhibitors*
  • ADP Ribose Transferases / metabolism*
  • Apoptosis / drug effects*
  • DNA Damage / drug effects*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Small Molecule Libraries
  • ADP Ribose Transferases
  • PARP10 protein, human
  • Poly(ADP-ribose) Polymerases