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U.S. National Institutes of Health
Cancer Diagnosis Program Cancer Imaging Program Cancer Therapy Evaluation Program Developmental Therapeutics Program Radiation Research Program Translational Research Program Biometric Research Branch Office of Cancer Complementary and Alternative Medicine

ABT-888 (NSC 737664)

Overview

DNA damaging agents are among the most successful treatments for cancer. The enzyme Poly(ADP-ribose)polymerase (abbreviated PARP) can facilitate repair of DNA damage caused by insult from chemotherapeutic agents and radiation. Increased PARP activity is associated with survival of some cancer cells. ABT-888, an orally bioavailable PARP-inhibitor developed by Abbott Laboratories, significantly enhanced the antitumor activity of DNA-damaging agents and radiation in preclinical models. Further development of this compound is ongoing.

Basic Chemistry

Preclinical Studies

  • in vitro
    • Biochemical Assays
      • Potency was determined in PARP-1 and PARP-2 enzyme assays where the Kis are 5.4 and 2.9 nM, respectively.
      • ABT-888 inhibits the PARP directed formation of its product, PAR, with an EC50 of 2.5 nM in cells.
  • in vivo
    • Efficacy Studies - In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.
    • Pharmacokinetic Studies
      • ABT-888 has good oral bioavailability, and readily crosses the blood-brain barrier.
      • ABT-888 profoundly inhibits the formation of PAR in tumors in xenograft models.

Clinical Studies

  • Investigational New Drug (IND) Information
    • CTEP Exploratory IND
    • Abbott Laboratories IND
  • Active and Closed Clinical Trials
    • ABT-888 has entered a Phase 0 trial for subjects with refractory solid tumors and lymphoid malignancies.
    • Phase I studies are expected to start in 2007.
    • Please see www.clinicaltrials.gov for information on clinical trials with ABT-888.