title: PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3.
abstract: Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Anders E G
authors.initials: AE
authors.lastname: Lindgren
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.forename: Mareike
authors.initials: M
authors.lastname: Hesse
authors.forename: Sara
authors.initials: S
authors.lastname: Spjut
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Pinto
authors.forename: Johan
authors.initials: J
authors.lastname: Weigelt
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; C587059:ME0328; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D052999:Quinazolinones; D009536:Niacinamide; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases; C105233:ART3 protein, human