ABT-888 (NSC 737664)
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.
- 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.
- 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.