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25mg |
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Purity: ≥98%
Veliparib dihydrochloride (also known as ABT888 dihydrochloride; ABT-888 dihydrochloride) is a novel and potent inhibitor of PARP1 and PARP2 [Poly (ADP-Ribose) Polymerase] with Ki of 5.2 nM and 2.9 nM in cell-free assays, respectively. It is inert against SIRT2 and exhibits chemosensitizing and antitumor properties. When combined with a range of cytotoxic agents, ABT-888 has shown excellent in vivo efficacy in a broad spectrum of preclinical tumor models. Compared to microsatellite stable (MSS) cell lines (wild-type for both genes), ABT-888 is also active on microsatellite instability (MSI) cell lines carrying mutations in both the MRE11 and RAD50 genes. At therapeutic concentrations, ABT-888 has no antiproliferative effects. Instead, it inhibits PARPs, which prevents DNA repair and increases the cytotoxicity of agents that damage DNA.
Targets |
PARP-2 ( Ki = 2.9 nM ); PARP-1 ( Ki = 5.2 nM )
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ln Vitro |
Veliparib exhibits no effect on SIRT2 (>5 μM). [1] With an EC50 of 2 nM, veliparib suppresses PARP activity in C41 cells[2]. In H460 cells exposed to and not exposed to light, veliparib lowers PAR levels. DNA repair and clonogenesis in H460 cells are inhibited by PARP-1 inhibition. When veliparib is combined with radiation therapy, H460 cells exhibit increased sequestration and autophagy [3]. In H1299, DU145, and 22RV1 cells, veliparib decreases PARP activity; this suppression is correlated with p53 function. In clonogenic H1299 cells, veliparib (10 μM) reduces quarter fraction (SF) by 43%. In oxygenated H1299 cells, velibib distributes radiation efficiently. In hypoxia-irradiated cells such H1299, DU145, and 22RV1, veliparib can disconnect SF[4].
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ln Vivo |
Veliparib has a 56%–92% postcranial bioavailability in mice, SD spray, beagle dogs, and cynomolgus monkeys[1]. Tumor growth delay is improved in the NCI-H460 xenograft model by veliparib (25 mg/kg, ip). Veliparib can lessen tumor vascularization when combined with radiation therapy [3]. Veliparib, at dosages of 3 and 12.5 mg/kg, decreased intratumoral PAR levels in A375 and Colo829 xenograft models by more than 95%; this suppression was reversible over time [4].
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Enzyme Assay |
In PARP assays, 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 are added to a buffer. After 1.5 mM benzamide is added to stop the reaction, the reaction is moved to streptavidin Flash plates and counted using a TopCount microplate scintillation counter.
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Animal Protocol |
In order to conduct syngeneic studies on B16F10, a mixture of 6×104 cells and 50% Matrigel is injected subcutaneously (20 g) into the flank of 6- to 8-week-old female C57BL/6 mice. In order to conduct cisplatin efficacy studies, fragments (20–30 mm3) of human tumors taken from spontaneously growing tumors in nude mouse hosts are trocar-implanted in female nude mice. In the studies involving carboplatin and MX-1 cyclophosphamide, 200 μL of a 1:10 dilution of tumor brei in 45% Matrigel and 45% Spinner MEM is administered to female scid mice as an injection. Tumors are allowed to grow to the specified size in these well-established tumor studies, after which they are randomized to therapy groups. Male scid mice are given a s.c. injection of 1×106 cells mixed with 50% Matrigel to be used in DOHH-2 xenograft studies. Veliparib is administered orally or continuously via s.c. insertion of a 14-day Alzet OMP model 2002 in a pH 4.0-adjusted 0.9% NaCl solution. Doses of Veliparib are determined based on the OMP's daily delivery rate of 12 μL. The formulation of temozolomide, cisplatin, carboplatin, and cyclophosphamide is done in accordance with the advice of the manufacturers.
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References |
[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 |
Molecular Formula |
C13H18CL2N4O
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Molecular Weight |
317.21
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Exact Mass |
316.09
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Elemental Analysis |
C, 49.22; H, 5.72; Cl, 22.35; N, 17.66; O, 5.04
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CAS # |
912445-05-7
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Appearance |
Solid powder
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SMILES |
C[C@@]1(CCCN1)C2=NC3=C(C=CC=C3N2)C(=O)N.Cl.Cl
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InChi Key |
DSBSVDCHFMEYBX-FFXKMJQXSA-N
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InChi Code |
InChI=1S/C13H16N4O.2ClH/c1-13(6-3-7-15-13)12-16-9-5-2-4-8(11(14)18)10(9)17-12;;/h2,4-5,15H,3,6-7H2,1H3,(H2,14,18)(H,16,17);2*1H/t13-;;/m1../s1
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Chemical Name |
2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;dihydrochloride
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.