1. Towards small molecule inhibitors of mono-ADP-ribosyltransferases
- Author
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Anders E. G. Lindgren, Rémi Caraballo, C. David Andersson, Ann-Gerd Thorsell, Herwig Schüler, Anna Linusson, Mikael Elofsson, T. Ekblad, Tobias Karlberg, and Sara Spjut
- Subjects
DNA repair ,Poly ADP ribose polymerase ,Drug Evaluation, Preclinical ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Protein degradation ,Small Molecule Libraries ,Inhibitory Concentration 50 ,PARP1 ,Drug Discovery ,Transcriptional regulation ,Humans ,Enzyme Inhibitors ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Pharmacology ,Diphtheria toxin ,ADP Ribose Transferases ,Poly(ADP-ribose) polymerase ,Chemistry ,ARTD inhibitor ,Organic Chemistry ,Mono-ADP-ribosyltransferase ,General Medicine ,Small molecule ,PARP inhibitor ,Biochemistry ,mART ,Diphtheria toxin-like ADP-ribosyltransferase - 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.
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