Abstract
Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments.
Veliparib (ABT-888) is being investigated to treat squamous and non-squamous non-small cell lung cancer, BRCA breast cancer, triple negative breast cancer and ovarian cancer.
Biological activity
Veliparib (ABT-888) 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. Phase 3.
In vitro
Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor，which inhibits PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM in cell-free assays，respectively.ABT-888 reduces clonogenic survival and inhibits DNA repair in H460 cells. ABT-888 inhibits the PARP activity with EC50 of 2 nM in C41 cells.
In vivo
ABT-888 inhibits PARP in B16F10 and 9L xenograft models, thus enhancing the anticancer activity of temozolomide. The Combined with other cytotoxic agents, ABT-888 shows strong antitumor effect in MX-1 xenograft model. ABT-888 reduces intratumor PAR levels by more than 95% at a dose of 3 and 12.5 mg/kg according to the the size of tumors in A375 and Colo829 xenograft models.
Features
ABT-888 enhances the effectiveness of common cancer treatments, such as radiation therapy and alkylating agents.
References
https://www.abbvie.com/our-science/pipeline/veliparib.html
https://en.wikipedia.org/wiki/Veliparib
Chemical Properties
Off-White Solid
Uses
ABT-888 is a potent, orally bioavailable PARP-1/-2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo.
Definition
ChEBI: A benzimidazole substituted with a carbamoyl group at C-4 and a (2R)-2-methylpyrrolidin-2-yl moiety at C-2. It is a potent, orally bioavailable PARP inhibitor.
Biological Activity
abt-888, also named as veliparib, is poly (adp-ribose) polymerase (parp) inhibitor and has demonstrated excellent in vivo efficacy in a broad spectrum of preclinical tumor models in combination with a variety of cytotoxic agents. parp is involved in dna repair and elevated parp levels can result in resistance to cytotoxic chemotherapy and radiation. so, parp inhibitors hold promise as chemotherapy and radiation sensitizers. abt-888 is also active on microsatellite instability (msi) cell lines harboring mutations in both mre11 and rad50 genes compared to microsatellite stable (mss) cell lines (wild-type for both genes).shivaani kummar, robert kinders, martin e. gutierrez, larry rubinstein, ralph e. parchment, lawrence r. phillips, jiuping ji, anne monks, jennifer a. low, alice chen, anthony j. murgo, jerry collins, seth m. steinberg, helen eliopoulos, vincent l. giranda, gary gordon, lee helman, robert wiltrout, joseph e. tomaszewski and james h. doroshow. phase 0
Synthesis
General procedure for the synthesis of 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide from the compound (CAS: 912443-99-3): (2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide was detected (0.0246 mol), which was found to contain 70% of 2-[(R)-2-methyl pyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide. To the reaction system 80 mL of anhydrous methanol was added, stirred and heated until dissolved. After cooling to about 40 °C, a solution consisting of 13.5 g (0.0345 mol) of (-)-di-p-toluoyl-L-tartaric acid (anhydrous) dissolved in 100 mL of anhydrous methanol was added. A white precipitate was rapidly precipitated and stirring was continued for about 2 hours. It was filtered and the filter cake was washed with anhydrous methanol. The undried filter cake was added to 80 mL of water, stirred and neutralized with base, followed by precipitation of a solid product. After continued stirring for 4 hours, it was filtered and the filter cake was washed three times with water, followed by vacuum drying. (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide was obtained, which was purified by HPLC to give 3.6 g of product with 99.7% HPLC purity and 99.8% chiral purity. The yield was 85.7%.
in vivo
Veliparib (ABT-888) is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier in syngeneic and xenograft tumor models[1]. In MDA-MB-231 xenograft tumor models, combination treatment (AG014699/PF-02341066 and Veliparib (ABT-888)/Foretinib) substantially reduced tumor growth compared to either inhibitor alone[2].
IC 50
PARP-2: 2.9 nM (Ki); PARP-1: 5.2 nM (Ki); Autophagy
References
[1] Patent: CN106432195, 2017, A. Location in patent: Paragraph 0040-0050
