Discovery of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor 2-[(<i>R</i>)-2-methylpyrrolidin-2-yl]-1<i>H</i>-benzimidazole-4-carboxamide (ABT-888) for the Treatment of Cancer

Penning, Thomas D.; Zhu, Gui‐Dong; Gandhi, Viraj B.; Gong, Jianchun; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Johnson, Eric F.; Donawho, Cherrie K.; Frost, David J.; Bontcheva-Diaz, Velitchka; Bouska, Jennifer J.; Osterling, Donald J.; Olson, Amanda M.; Marsh, Kennan C.; Luo, Yan; Giranda, Vincent L.

doi:10.1021/jm801171j

Cited by 241 publications

(175 citation statements)

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“…Veliparib and its lactam metabolite (M8) were synthesized as described previously (Penning et al, 2009 (10:90, v/v) to make a dosing solution at a final concentration of 5 mg/ml. The dose volume was 1.0 ml/kg for rats and 0.5 ml/kg for dogs for both intravenous and oral dosing.…”

Section: Methodsmentioning

confidence: 99%

“…1) is a novel and potent inhibitor of PARP-1 and PARP-2 enzymes (K i of 5 and 2 nM, respectively) and has demonstrated excellent in vivo efficacy in a broad spectrum of preclinical tumor models in combination with a variety of cytotoxic agents such as temozolomide (TMZ), cisplatin, cyclophosphamide, and radiation (Donawho et al, 2007;Palma et al, 2009;Penning et al, 2009). Preclinical pharmacokinetic profiles of veliparib were characterized by high plasma clearance, high volumes of distribution, and high oral bioavailability across species (Donawho et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Li¹,

Delzer²,

Voorman³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The Veliparib absorption was high. Dosed radioactivity was widely distributed in rat tissues. The majority of drug-related material was excreted in urine as unchanged drug (approximately 54, 41, and 70% of the dose in rats, dogs, and humans, respectively). A lactam M8 and an amino acid M3 were two major excretory metabolites in animals. In the circulation of animals and humans, veliparib was the major drug-related component, and M8 was one of the major metabolites. Monooxygenated metabolite M2 was significant in the rat and dog, and M3 was also significant in the dog. Veliparib biotransformation occurred on the pyrrolidine moiety via formation of a lactam, an amino acid, and an N-carbamoyl glucuronide, in addition to oxidation on benzoimidazole carboxamide and sequential glucuronidation. In vitro experiments using recombinant human cytochrome P450 (P450) enzymes identified CYP2D6 as the major enzyme metabolizing veliparib with minor contributions from CYP1A2, 2C19, and 3A4. Veliparib did not inhibit or induce the activities of major human P450s. Veliparib was a weak P-glycoprotein (P-gp) substrate, showing no P-gp inhibition. Taken together, these studies indicate a low potential for veliparib to cause clinically significant P-gp or P450-mediated drug-drug interactions (DDIs). Overall, the favorable dispositional and DDI profiles of veliparib should be beneficial to its safety and efficacy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Li¹,

Delzer²,

Voorman³

et al. 2011

Drug Metab Dispos

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“…To test these predictions, we incubated PEO1 cells with the PARP inhibitor ABT-888 (22) (Fig. 2A) and examined the phosphorylation of DNA-PK substrates.…”

Section: Parp Inhibitor Synthetic Lethality Is Independent Of Xrcc1 Amentioning

confidence: 99%

Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells

Patel

Sarkaria

Kaufmann

2011

Proc. Natl. Acad. Sci. U.S.A.

475

431

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Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HRdeficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR-deficient cells treated with PARP inhibitors.chemotherapy | DNA repair | synthetic lethality | double-strand break repair P oly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear enzyme that synthesizes poly(ADP-ribose) polymer when activated by DNA nicks or breaks. Activation of PARP1 has important effects on a variety of cellular processes, including base excision repair (BER), transcription, and cellular bioenergetics (1). The role of PARP1 in the DNA damage response sparked interest in the development of PARP inhibitors as potential chemosensitizers for the treatment of cancer (1, 2). The more recent observation that PARP inhibition is particularly lethal to cells deficient in homologous recombination (HR) proteins (3-8) has generated additional excitement in the cancer chemotherapy community. The current explanation for this hypersensitivity focuses on a mechanism (Fig. 1A) in which loss of PARP1 activity is thought to result in accumulation of DNA single-strand breaks (SSBs), which are subsequently converted to DNA double-strand breaks (DSBs) by the cellular replication and/or transcription machinery. These DSBs, which are repaired by HR in BRCApositive cells, are presumed to accumulate in BRCA1-or BRCA2-deficient cells, leading to subsequent cell death. Heightened sensitivity to PARP inhibition has also been observed in cells with other genetic lesions that affect HR, including phosphatase and tensin homolog (PTEN) deficiency (5), ataxia telangiectasia mutated (ATM) deficiency (7,8), and Aurora A overexpression (6).Although the preceding studies underscore the importance of PARP1 and HR in maintaining genomic stability, they do not address the role of nonhomologous end joining (NHEJ), an alternate DSB repair modality that directly joins broken ends of DNA with little or no regard for sequence homology (9). NHEJ is initiated when free DNA ends are bound by Ku70 and Ku80, which recruit the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). The resulting complex, known as the DNAdependent protein kinase (DNA-PK) complex, phosphorylates downstream targe...

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“…Veliparib is an orally administered, potent inhibitor of PARP1 and 2 (4). In preclinical studies, veliparib has demonstrated increased cytotoxicity when given in combination with DNAdamaging agents such as platinum compounds, topoisomerase inhibitors, and alkylating agents (5-7).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer

Ramalingam

Blais

Mazières³

et al. 2017

Clinical Cancer Research

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Purpose: PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non-small cell lung cancer.Experimental Design: Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo. Veliparib (120 mg) or placebo was given on days 1 to 7 of each 3-week cycle, with carboplatin (AUC ¼ 6 mg/mL/min) and paclitaxel (200 mg/m 2 ) administered on day 3, for a maximum of 6 cycles. Results: Overall, 158 were included (median age, 63 years; male 68%, squamous histology 48%). Median PFS was 5.8 months in the veliparib group versus 4.2 months in the placebo group [HR, 0.72; 95% confidence interval (CI), 0.45-1.15; P ¼ 0.17)]. Median overall survival (OS) was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54-1.18; P ¼ 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26-1.12; P ¼ 0.098) and OS (HR, 0.73; 95% CI, 0.43-1.24; P ¼ 0.24) favored veliparib treatment. Objective response rate was similar between groups (veliparib: 32.4%; placebo: 32.1%), but duration of response favored veliparib treatment (HR, 0.47; 95% CI, 0.16-1.42; P ¼ 0.18). Grade III/IV neutropenia, thrombocytopenia, and anemia were comparable between groups.Conclusions: Veliparib combination with carboplatin and paclitaxel was well-tolerated and demonstrated a favorable trend in PFS and OS versus chemotherapy alone. Patients with squamous histology had the best outcomes with veliparib combination.

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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

Cited by 241 publications

References 28 publications

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells

Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer

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