Veliparib (ABT-888)

2 years -80 in solvent

Orally administered

A Phase I study of evaluating the bioavailability and food effect of three formulations of ABT-888 on pharmacokinetics in subjects with solid tumors has been completed.

Formulated in solution containing 0.9% NaCl adjusted to pH 4.0

ABT-888 is inactive to SIRT2 (>5 uM). [1] ABT-888 inhibits the PARP activity with EC50 of 2 nM in C41 cells. [2] ABT-888 could decrease the PAR levels in both irradiated and nonirradiated H460 cells., ABT-888 also reduces clonogenic survival and inhibits DNA repair by PARP-1 inhibition in H460 cells. ABT-888 increases apoptosis and autophagy in H460 cells when combination with radiation. [3] ABT-888 also inhibits PARP activity in H1299, DU145 and 22RV1 cells and the inhibition is independent of p53 function. ABT-888 (10 uM) suppresses the surviving fraction (SF) by 43% in the clonogenic H1299 cells. ABT-888 shows effective radiosensitivity in oxic H1299 cells., Furthermore, ABT-888 could attenuate the SF of hypoxic-irradiated cells including H1299, DU145 and 22RV1. [4]

In vitro PARP assays, PARP assays are conducted in a buffer containing 50 mM Tris (pH 8.0), 1 mM DTT, 1.5 uM [3H]NAD+ (1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM slDNA, and 1 nM PARP-1 or 4 nM PARP-2 enzyme. Reactions are terminated with 1.5 mM benzamide, transferred to streptavidin Flash plates, and counted using a TopCount microplate scintillation counter.

Veliparib (ABT-888, NSC 737664) is a potent inhibitor of PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM in cell-free assays, respectively. It is inactive to SIRT2. Veliparib increases autophagy and apoptosis. Phase 3.

ABT-888 is developed to increase the effectiveness of common cancer therapies such as radiation and alkylating agents.