Towards small molecule inhibitors of mono-ADP-ribosyltransferases

Eur J Med Chem. 2015 May 5:95:546-51. doi: 10.1016/j.ejmech.2015.03.067. Epub 2015 Apr 1.

Abstract

Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

Keywords: ARTD inhibitor; Diphtheria toxin-like ADP-ribosyltransferase; Mono-ADP-ribosyltransferase; PARP inhibitor; Poly(ADP-ribose) polymerase; mART.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / antagonists & inhibitors*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Small Molecule Libraries / pharmacology*

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • ADP Ribose Transferases