ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

  title={ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models},
  author={Cherrie K. Donawho and Yan Luo and Yanping Luo and Thomas D Penning and Joy L. Bauch and Jennifer J. Bouska and Velitchka Bontcheva-Diaz and Bryan F. Cox and Theodore DeWeese and Larry E. Dillehay and Debra C. Ferguson and Nayereh S. Ghoreishi-Haack and David R. Grimm and Ran Guan and Edward Kyu-ho Han and Rhonda R. Holley-Shanks and Boris Hristov and Kenneth B. Idler and Kenneth P. Jarvis and Eric F. Johnson and Lawrence R Kleinberg and Vered Klinghofer and Loren M. Lasko and Xuesong Mike Liu and Kennan Marsh and Thomas Mcgonigal and Jonathan A. Meulbroek and Amanda M. Olson and Joann P. Palma and Luis E. Rodriguez and Yan Shi and Jason A. Stavropoulos and Alan C. Tsurutani and Gui-dong Zhu and Saul H. Rosenberg and Vincent L. Giranda and David J. Frost},
  journal={Clinical Cancer Research},
  pages={2728 - 2737}
Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design:In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with Kis of 5.2 and 2.9 nmol/L… 

Figures and Tables from this paper

In vitro and in vivo enhancement of chemoradiation using the oral PARP inhibitor ABT-888 in colorectal cancer cells.
Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma
ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy and the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.
The poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide suppresses cell growth and migration, enhancing suppressive effects of cisplatin in osteosarcoma cells.
The results indicated that 3-AB suppressed U2OS cell growth in a time- and dose-dependent manner, and the suppressive effects of3-AB were associated with increased cell apoptosis, suggesting that this PARP-1 inhibitor may be developed into an effective agent for the treatment of human osteosarcoma.
MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation
MK-4827 shows high potential to improve the efficacy of radiotherapy and reduces PAR levels in tumors by 1 h after administration which persisted for up to 24 h, which potentially adds to the flexibility of design of future clinical trials.
Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic and show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomersase I inhibitor, topotecan, in PBMCs, tumor, and CTCs.
Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy
Data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.
Oral Poly(ADP-Ribose) Polymerase-1 Inhibitor BSI-401 Has Antitumor Activity and Synergizes with Oxaliplatin against Pancreatic Cancer, Preventing Acute Neurotoxicity
BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.
Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors
Understanding the context-specific relationships of trapping and catalytic inhibition with both tolerability and efficacy will aid in determining the suitability of a PARP inhibitor for inclusion in a particular clinical regimen.
BMN 673, a Novel and Highly Potent PARP1/2 Inhibitor for the Treatment of Human Cancers with DNA Repair Deficiency
BMN 673 exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparIB, and veliparib), and represents a promising PARP2 inhibitor with potentially advantageous features in its drug class.


Oral administration of PARP inhibitor GPI 18180 increases the anti-tumor activity of temozolomide against intracranial melanoma in mice
Oral administration of GPI 18180 enhances the effect of TMZ against melanoma in mouse brain, and warrants its further development towards clinical evaluation.
Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma.
  • L. Tentori, C. Leonetti, G. Graziani
  • Medicine, Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2003
Systemic administration of the poly(ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site.
Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361.
AG14361 is, to the authors' knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines.
  • C. Delaney, L. Wang, D. Newell
  • Biology, Chemistry
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2000
The data demonstrate that PARP inhibitors are effective resistance-modifying agents in human tumor cell lines and have provided a comprehensive assessment protocol for the selection of optimum combinations of anticancer drugs, PARP inhibitor, and cell lines for in vivo studies.
Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor.
Exposure of tumor cells to TMZ, camptothecin, and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary.
Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells
Investigation of the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells found that PARP-1 inhibition represents a novel way of selectively targeting such tumors.
Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1.
There was a correlation between the ability of the inhibitors to prevent IR-induced DNA DSB repair and their ability to potentiate cytotoxicity and the DNA-PK and PARP-1 inhibitors show potential as tools for anticancer therapeutic intervention.
Chemopotentiation by PARP inhibitors in cancer therapy.
Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies
The maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias were determined and a previously undescribed nonsynonymous single nucleotide polymorphism was identified in exon 4 of the β-tubulin gene, TUBB, in three other patients.
The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors
The double-edged sword roles of PARP in DNA damage signaling and cell death are reviewed and the underlying mechanisms of the anti-inflammatory effects ofPARP inhibitors are summarized.