title: Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
abstract: Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Mirjam
authors.initials: M
authors.lastname: Löw
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Pinto
authors.forename: Lionel
authors.initials: L
authors.lastname: Trésaugues
authors.forename: Martin
authors.initials: M
authors.lastname: Moche
authors.affiliation: Program in Chemical Biology and Department of Physiology and Pharmacology, Health & Science University , Portland, Oregon 97210, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Herwig
authors.identifier: 0000-0003-4059-3501
authors.initials: H
authors.lastname: Schüler
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007191:Indazoles; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D010793:Phthalazines; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C586365:talazoparib; D011065:Poly(ADP-ribose) Polymerases; D038501:Tankyrases; C545685:niraparib; C531550:olaparib