New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target

J Med Chem. 2013 Sep 26;56(18):7431-41. doi: 10.1021/jm4010187. Epub 2013 Sep 12.


Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Binding, Competitive*
  • Catalytic Domain
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA Nucleotidylexotransferase / antagonists & inhibitors*
  • DNA Nucleotidylexotransferase / chemistry
  • DNA Nucleotidylexotransferase / metabolism*
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / metabolism
  • Deoxyadenine Nucleotides / metabolism
  • Dideoxynucleotides / metabolism
  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Hexuronic Acids / chemistry
  • Hexuronic Acids / metabolism
  • Hexuronic Acids / pharmacology
  • Humans
  • Models, Molecular
  • Nucleotides / metabolism*


  • DNA, Single-Stranded
  • Deoxyadenine Nucleotides
  • Dideoxynucleotides
  • Enzyme Inhibitors
  • Hexuronic Acids
  • Nucleotides
  • hexenuronic acid
  • 2',3'-dideoxyadenosine triphosphate
  • DNA Nucleotidylexotransferase

Associated data

  • PDB/4IQT
  • PDB/4IQU
  • PDB/4IQV
  • PDB/4IQW