2. Academic Validation
  3. Towards small molecule inhibitors of mono-ADP-ribosyltransferases

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.
Torun Ekblad 1,  Anders E G Lindgren 2,  C David Andersson 2,  Rémi Caraballo 2,  Ann-Gerd Thorsell 1,  Tobias Karlberg 1,  Sara Spjut 2,  Anna Linusson 2,  Herwig Schüler 3,  Mikael Elofsson 4
Affiliations

Affiliations

  • 1 Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
  • 2 Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • 3 Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Electronic address: [email protected].
  • 4 Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. Electronic address: [email protected].
PMID: 25847771 DOI: 10.1016/j.ejmech.2015.03.067
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.

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