Veliparib dihydrochloride(Synonyms: 维利帕尼二盐酸盐; ABT-888 dihydrochloride)

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Veliparib dihydrochloride (Synonyms: 维利帕尼二盐酸盐; ABT-888 dihydrochloride) 纯度: 99.96%

Veliparib dihydrochloride是有效的 PARP1PARP2 抑制剂,Ki 分别为5.2 nM,2.9 nM。

Veliparib dihydrochloride(Synonyms: 维利帕尼二盐酸盐; ABT-888 dihydrochloride)

Veliparib dihydrochloride Chemical Structure

CAS No. : 912445-05-7

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生物活性

Veliparib (dihydrochloride) is a potent inhibitor of PARP1 and PARP2 with Kis of 5.2 nM and 2.9 nM in cell-free assays, respectively.

IC50 & Target[1]

PARP-2

2.9 nM (Ki)

PARP-1

5.2 nM (Ki)

体外研究
(In Vitro)

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

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

The oral bioavailability of Veliparib is 56%-92% in mice, SD rats, beagle dogs, and cynomolgus monkeys after oral administration[1]. Veliparib (25 mg/kg, i.p.) can improve tumor growth delay in a NCI-H460 xenograft model. Combination with radiation, veliparib decreases the tumor vessel formation[3]. Veliparib reduces intratumor PAR levels by more than 95% at a dose of 3 and 12.5 mg/kg in A375 and Colo829 xenograft models and the suppression can be maintained over time[4].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

分子量

317.21

Formula

C13H18Cl2N4O

CAS 号

912445-05-7

中文名称

维利帕尼二盐酸盐

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式

4°C, sealed storage, away from moisture

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

溶解性数据
In Vitro: 

H2O : 250 mg/mL (788.12 mM; Need ultrasonic)

DMSO : ≥ 3.2 mg/mL (10.09 mM)

* “≥” means soluble, but saturation unknown.

配制储备液
浓度 溶剂体积 质量 1 mg 5 mg 10 mg
1 mM 3.1525 mL 15.7624 mL 31.5249 mL
5 mM 0.6305 mL 3.1525 mL 6.3050 mL
10 mM 0.3152 mL 1.5762 mL 3.1525 mL

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效
储备液的保存方式和期限:-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)。-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。

参考文献
  • [1]. Donawho CK, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37.

    [2]. Penning TD, et al. Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem. 2009 Jan 22;52(2):514-23.

    [3]. Albert JM, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res. 2007 May 15;13(10):3033-42.

    [4]. Robert J. Kinders, et al. Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse Xenografts. Clin Cancer Res. Author manuscript; available in PMC 2009 Nov 1.

Kinase Assay
[1]

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.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

For B16F10 syngeneic studies, 6×104 cells are mixed with 50% Matrigel and inoculated by s.c. injection into the flank of 6- to 8-week-old female C57BL/6 mice (20 g). For cisplatin efficacy studies, female nude mice are implanted s.c. by trocar with fragments (20-30 mm3) of human tumors harvested from s.c. grown tumors in nude mice hosts. For the carboplatin and MX-1 cyclophosphamide studies, female scid mice are inoculated with 200 μL of a 1:10 dilution of tumor brei in 45% Matrigel and 45% Spinner MEM. For these established tumor studies, tumors are allowed to grow to the indicated size and then randomized to therapy groups. For DOHH-2 xenograft studies, 1×106 cells are mixed with 50% Matrigel and inoculated by s.c. injection into the flank of male scid mice. Veliparib is delivered by either oral route or continuous infusion using s.c. placement of 14-day Alzet OMP model 2002 in a vehicle containing 0.9% NaCl adjusted to pH 4.0. The OMP delivers at a rate of 12 μL daily and Veliparib doses are calculated accordingly. Temozolomide, cisplatin, carboplatin, and cyclophosphamide are formulated according to the manufacturers’ recommendations.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献
  • [1]. Donawho CK, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37.

    [2]. Penning TD, et al. Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem. 2009 Jan 22;52(2):514-23.

    [3]. Albert JM, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res. 2007 May 15;13(10):3033-42.

    [4]. Robert J. Kinders, et al. Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse Xenografts. Clin Cancer Res. Author manuscript; available in PMC 2009 Nov 1.

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