title: Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres.
abstract: PARP-family ADP-ribosyltransferases (PARPs) and sirtuin deacetylases all use NAD(+) as cosubstrate for ADP-ribosyl transfer. PARP inhibitors are important research tools and several are being evaluated in cancer treatment. With the exception of a few tankyrase inhibitors, all current PARP inhibitors mimic the nicotinamide moiety in NAD(+) and block the nicotinamide binding pocket. We report here that while the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are blocked by sirtuin inhibitor Ex527 in vitro, they are unaffected by the seven clinical and commonly used PARP inhibitors niraparib, olaparib, rucaparib, talazoparib, veliparib, PJ34, and XAV939. These findings indicate that PARP inhibitors containing planar nicotinamide mimetics do not bind to sirtuin cofactor sites. In conclusion, a simple commercially available assay can be used to rule out interference of novel PARP inhibitors with sirtuin NAD(+) binding.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177, Stockholm, Sweden.
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177, Stockholm, Sweden.
authors.forename: Herwig
authors.identifier: http://orcid.org/0000-0003-4059-3501
authors.initials: H
authors.lastname: Schüler
mesh_terms: D006801:Humans; D009536:Niacinamide / Q000737:chemistry*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide
keywords: chemical biology; structure-based drug design; therapeutic target