title: BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.
abstract: OBJECTIVE
  PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties.
  
  
  METHODS
  Potency and selectivity of BMN 673 was determined by biochemical assays. Anticancer activity either as a single-agent or in combination with other antitumor agents was evaluated both in vitro and in xenograft cancer models.
  
  
  RESULTS
  BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nmol/L), but it does not inhibit other enzymes that we have tested. BMN 673 exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparib, and veliparib). In vitro, BMN 673 selectively targeted tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable antitumor activity in vivo; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency were profoundly sensitive to oral BMN 673 treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects were also found when BMN 673 was combined with temozolomide, SN38, or platinum drugs.
  
  
  CONCLUSIONS
  BMN 673 is currently in early-phase clinical development and represents a promising PARP1/2 inhibitor with potentially advantageous features in its drug class.
authors.affiliation: Authors' Affiliations: BioMarin Pharmaceutical Inc., Novato, California; Cancer Research UK Gene Function Laboratory; and The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.forename: Farah L
authors.initials: FL
authors.lastname: Rehman
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Julia
authors.initials: J
authors.lastname: Boshuizen
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Post
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D049914:DNA Repair-Deficiency Disorders / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010793:Phthalazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C586365:talazoparib; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases