Veliparib dihydrochloride (ABT-888 dihydrochloride) 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.

PARP1:5.2 nM (Ki), PARP2:2.9 nM(Ki)

Veliparib对SIRT2无活性(>5 μM)[1]。在C41细胞中，Veliparib抑制PARP活性，EC50为2 nM[2]。Veliparib能降低受照射和未受照射的H460细胞中的PAR水平，减少其克隆形成存活率，并通过抑制PARP-1来抑制DNA修复[3]。当与辐射结合时，Veliparib在H460细胞中增加凋亡和自噬[3]。Veliparib在H1299、DU145和22RV1细胞中抑制PARP活性，该抑制作用与p53功能无关。Veliparib (10 μM)在H1299克隆形成细胞中抑制存活分数(SF)43%。Veliparib在有氧的H1299细胞中展现出有效的放射敏感性。Veliparib还能减弱包括H1299、DU145和22RV1在内的低氧照射细胞的SF[4]。

Veliparib的口服生物利用度在小鼠、SD大鼠、比格犬和猕猴中为56%-92%，经口给药后[1]。Veliparib (25 mg/kg, i.p.) 能在NCI-H460异种移植模型中改善肿瘤生长延迟。当与辐射结合时，Veliparib可减少肿瘤血管形成[3]。在A375和Colo829异种移植模型中，Veliparib以3和12.5 mg/kg的剂量降低肿瘤内PAR水平超过95%，且抑制效果能够持续[4]。

PARP assays are conducted in a buffer containing 50 mM Tris (pH 8.0), 1 mM DTT, 1.5 μM [3H]NAD+?(1.6 μCi/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.