Sunday, April 19, 2015

Drugs in Clinical Pipeline: Veliparib

Veliparib [(R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide] is an investigational oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor being evaluated in multiple tumor types. Veliparib has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate.

Veliparib is developed by AbbVie. AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories.

Common Name: Veliparib
Synonyms: ABT-888; ABT888; ABT 888
IUPAC Name: (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide
CAS Number: 912444-00-9
Mechanism of Action: PARP Inhibitor; PARP1 Inhibitor; PARP2 Inhibitor 
Indication: Activity against various tumors
Development Stage: Phase I/II
Company: AbbVie

Veliparib is a potent inhibitor of both PARP-1 and PARP-2 with Ki's of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. Veliparib strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at Veliparib doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), Veliparib potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, Veliparib potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, Veliparib did not display single-agent activity [1, 2].

1. Donawho, C. K.; 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, 13(9), 2728-2737.
2. Penning, T. D.; 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, 52(2), 514-523.