title: ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
abstract: OBJECTIVE
  To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.
  
  
  METHODS
  In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.
  
  
  RESULTS
  ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.
  
  
  CONCLUSIONS
  ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064-6074, USA.
authors.forename: Cherrie K
authors.initials: CK
authors.lastname: Donawho
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Joy L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Velitchka D
authors.initials: VD
authors.lastname: Bontcheva-Diaz
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Theodore L
authors.initials: TL
authors.lastname: DeWeese
authors.forename: Larry E
authors.initials: LE
authors.lastname: Dillehay
authors.forename: Debra C
authors.initials: DC
authors.lastname: Ferguson
authors.forename: Nayereh S
authors.initials: NS
authors.lastname: Ghoreishi-Haack
authors.forename: David R
authors.initials: DR
authors.lastname: Grimm
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Edward K
authors.initials: EK
authors.lastname: Han
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Holley-Shanks
authors.forename: Boris
authors.initials: B
authors.lastname: Hristov
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Idler
authors.forename: Ken
authors.initials: K
authors.lastname: Jarvis
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Kleinberg
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Loren M
authors.initials: LM
authors.lastname: Lasko
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Thomas P
authors.initials: TP
authors.lastname: McGonigal
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Meulbroek
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Olson
authors.forename: Joann P
authors.initials: JP
authors.lastname: Palma
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Jason A
authors.initials: JA
authors.lastname: Stavropoulos
authors.forename: Alan C
authors.initials: AC
authors.lastname: Tsurutani
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004195:Disease Models, Animal; D004285:Dogs; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib