title: Towards small molecule inhibitors of mono-ADP-ribosyltransferases.
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.
authors.affiliation: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Anders E G
authors.initials: AE
authors.lastname: Lindgren
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Rémi
authors.initials: R
authors.lastname: Caraballo
authors.affiliation: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.affiliation: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Spjut
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
authors.affiliation: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Electronic address: herwig.schuler@ki.se.
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. Electronic address: mikael.elofsson@chem.umu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D036002:ADP Ribose Transferases
keywords: ARTD inhibitor; Diphtheria toxin-like ADP-ribosyltransferase; Mono-ADP-ribosyltransferase; PARP inhibitor; Poly(ADP-ribose) polymerase; mART