title: Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination.
abstract: Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.
authors.affiliation: †Istituto di Ricerche di Biologia Molecolare, Via Pontina km 30600, 00040 Pomezia, Italy.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.affiliation: ‡TESARO, Inc., 1000 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Wilcoxen
authors.affiliation: †Istituto di Ricerche di Biologia Molecolare, Via Pontina km 30600, 00040 Pomezia, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.affiliation: †Istituto di Ricerche di Biologia Molecolare, Via Pontina km 30600, 00040 Pomezia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C545685:niraparib