Veliparib (ABT-888)
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.
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Providing storage is as stated on the product vial and the vial is kept tightly sealed, the product can be stored for up to
24 months(2-8C).
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J Med Chem,2009 Jan 22;52(2):514-23.
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.[Pubmed:
19143569]
We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system.
METHODS AND RESULTS:
These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.
Clin Cancer Res, 2007 May 15;13(10):3033-42.
Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models.[Pubmed:
17505006]
Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation.
METHODS AND RESULTS:
We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature.ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis.
CONCLUSIONS:
We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.
Clin Cancer Res,2007 May 1;13(9):2728-37.
ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.[Pubmed:
17473206]
Animal Models: NCI-H460, H460, B16F10 and 9L xenografts in C57BL/6 mice
Dosages:~25 mg/kg
Administration: Orally administered
