MedKoo product information:

Veliparib

Veliparib (ABT-888) is a poly(ADP-ribose) polymerase (PARP) -1 and -2 inhibitor with chemosensitizing and antitumor activities. With no antiproliferative effects as a single agent at therapeutic concentrations, ABT-888 inhibits PARPs, thereby inhibiting DNA repair and potentiating the cytotoxicity of DNA-damaging agents. PARP nuclear enzymes are activated by DNA single or double strand breaks, resulting in the poly(ADP-ribosyl)ation of other nuclear DNA binding proteins involved in DNA repair; poly(ADP-ribosyl)ation contributes to efficient DNA repair and to survival of proliferating cells exposed to mild genotoxic stresses as induced by as oxidants, alkylating agents or ionizing radiation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Abbott Laboratories.

Phase I study of  ABT-888 plus topotecan in adults with refractory solid tumors and lymphomas.  ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic. (source: Cancer Res. 2011 Sep 1;71(17):5626-34.).

Development status: According to wikipedia.com,  there are numerous phase I clinical trials  in progress for Veliparid (ABT-888).  A phase I/II clinical trial for use with/out doxorubicin (for Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma) started in 2008 and was due to complete in 2010.   A phase II clinical trial for metastatic melanoma has started recruiting, was due to end Dec 2011. A phase II clinical trial for metastatic breast cancer has started recruiting, and  was due to end Nov 2011. It will be included in the forthcoming I-SPY2 breast cancer trial. (source: http://en.wikipedia.org/wiki/Veliparib).

1: Ji J, Kinders RJ, Zhang Y, Rubinstein L, Kummar S, Parchment RE, Tomaszewski JE, Doroshow JH. Modeling pharmacodynamic response to the poly(ADP-Ribose) polymerase inhibitor ABT-888 in human peripheral blood mononuclear cells. PLoS One. 2011;6(10):e26152. Epub 2011 Oct 10. PubMed PMID: 22028822; PubMed Central PMCID: PMC3189959.

2: Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, Jia L, Weil M, Speranza G, Murgo AJ, Kinders R, Wang L, Parchment RE, Carter J, Stotler H, Rubinstein L, Hollingshead M, Melillo G, Pommier Y, Bonner W, Tomaszewski JE, Doroshow JH. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011 Sep 1;71(17):5626-34. Epub 2011 Jul 27. PubMed PMID: 21795476; PubMed Central PMCID: PMC3166628.

3: Nowsheen S, Bonner JA, Yang ES. The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy. Radiother Oncol. 2011 Jun;99(3):331-8. Epub 2011 Jun 28. PubMed PMID: 21719137; PubMed Central PMCID: PMC3157293.

4: Li X, Delzer J, Voorman R, de Morais SM, Lao Y. Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly(ADP-ribose) polymerase. Drug Metab Dispos. 2011 Jul;39(7):1161-9. Epub 2011 Mar 24. PubMed PMID: 21436403.

5: Karlberg T, Hammarström M, Schütz P, Svensson L, Schüler H. Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888. Biochemistry. 2010 Feb 16;49(6):1056-8. PubMed PMID: 20092359.

6: Reinhardt S, Zhao M, Mnatsakanyan A, Xu L, Ricklis RM, Chen A, Karp JE, Rudek MA. A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS. J Pharm Biomed Anal. 2010 May 1;52(1):122-8. Epub 2009 Dec 29. PubMed PMID: 20071126; PubMed Central PMCID: PMC2822340.

7: Phillips LR, Hill KD, Majerova E. Liquid Chromatographic Determination of NSC 737664 (ABT-888: an Inhibitor of Poly(ADP-ribose) Polymerase (PARP)) in Plasma and Urine in a Phase 0 Clinical Trial. J Liq Chromatogr Relat Technol. 2009 Jan;32(2):261-272. PubMed PMID: 20046211; PubMed Central PMCID: PMC2615403.

8: Wiegand R, Wu J, Sha X, LoRusso P, Li J. Simultaneous determination of ABT-888, a poly (ADP-ribose) polymerase inhibitor, and its metabolite in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 1;878(3-4):333-9. Epub 2009 Nov 27. PubMed PMID: 20005184.

9: Palma JP, Wang YC, Rodriguez LE, Montgomery D, Ellis PA, Bukofzer G, Niquette A, Liu X, Shi Y, Lasko L, Zhu GD, Penning TD, Giranda VL, Rosenberg SH, Frost DJ, Donawho CK. ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors. Clin Cancer Res. 2009 Dec 1;15(23):7277-90. Epub 2009 Nov 24. PubMed PMID: 19934293.

10: Liu X, Han EK, Anderson M, Shi Y, Semizarov D, Wang G, McGonigal T, Roberts L, Lasko L, Palma J, Zhu GD, Penning T, Rosenberg S, Giranda VL, Luo Y, Leverson J, Johnson EF, Shoemaker AR. Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. Mol Cancer Res. 2009 Oct;7(10):1686-92. Epub 2009 Oct 13. PubMed PMID: 19825992.

11: Yang SX, Kummar S, Steinberg SM, Murgo AJ, Gutierrez M, Rubinstein L, Nguyen D, Kaur G, Chen AP, Giranda VL, Tomaszewski JE, Doroshow JH; National Cancer Institute Phase 0 Working Group. Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas. Cancer Biol Ther. 2009 Nov;8(21):2004-9. Epub 2009 Nov 25. PubMed PMID: 19823047.

12: Horton TM, Jenkins G, Pati D, Zhang L, Dolan ME, Ribes-Zamora A, Bertuch AA, Blaney SM, Delaney SL, Hegde M, Berg SL. Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity. Mol Cancer Ther. 2009 Aug;8(8):2232-42. Epub 2009 Aug 11. PubMed PMID: 19671751.

13: Muscal JA, Thompson PA, Giranda VL, Dayton BD, Bauch J, Horton T, McGuffey L, Nuchtern JG, Dauser RC, Gibson BW, Blaney SM, Su JM. Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates. Cancer Chemother Pharmacol. 2010 Feb;65(3):419-25. Epub 2009 Jun 13. PubMed PMID: 19526240; PubMed Central PMCID: PMC2953793.

14: Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, Ji J, Monks A, Low JA, Chen A, Murgo AJ, Collins J, Steinberg SM, Eliopoulos H, Giranda VL, Gordon G, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009 Jun 1;27(16):2705-11. Epub 2009 Apr 13. PubMed PMID: 19364967; PubMed Central PMCID: PMC2739635.

15: Clarke MJ, Mulligan EA, Grogan PT, Mladek AC, Carlson BL, Schroeder MA, Curtin NJ, Lou Z, Decker PA, Wu W, Plummer ER, Sarkaria JN. Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Mol Cancer Ther. 2009 Feb;8(2):407-14. Epub 2009 Jan 27. PubMed PMID: 19174557; PubMed Central PMCID: PMC2692390.

16: Penning TD, Zhu GD, Gandhi VB, Gong J, Liu X, Shi Y, Klinghofer V, Johnson EF, Donawho CK, Frost DJ, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. 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 Jan 22;52(2):514-23. PubMed PMID: 19143569.

17: Palma JP, Rodriguez LE, Bontcheva-Diaz VD, Bouska JJ, Bukofzer G, Colon-Lopez M, Guan R, Jarvis K, Johnson EF, Klinghofer V, Liu X, Olson A, Saltarelli MJ, Shi Y, Stavropoulos JA, Zhu GD, Penning TD, Luo Y, Giranda VL, Rosenberg SH, Frost DJ, Donawho CK. The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res. 2008 Sep-Oct;28(5A):2625-35. PubMed PMID: 19035287.

18: Liu X, Shi Y, Guan R, Donawho C, Luo Y, Palma J, Zhu GD, Johnson EF, Rodriguez LE, Ghoreishi-Haack N, Jarvis K, Hradil VP, Colon-Lopez M, Cox BF, Klinghofer V, Penning T, Rosenberg SH, Frost D, Giranda VL, Luo Y. Potentiation of temozolomide cytotoxicity by poly(ADP)ribose polymerase inhibitor ABT-888 requires a conversion of single-stranded DNA damages to double-stranded DNA breaks. Mol Cancer Res. 2008 Oct;6(10):1621-9. PubMed PMID: 18922977.

19: Parise RA, Shawaqfeh M, Egorin MJ, Beumer JH. Liquid chromatography-mass spectrometric assay for the quantitation in human plasma of ABT-888, an orally available, small molecule inhibitor of poly(ADP-ribose) polymerase. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 1;872(1-2):141-7. Epub 2008 Jul 31. PubMed PMID: 18692448; PubMed Central PMCID: PMC2634284.

20: Liu SK, Coackley C, Krause M, Jalali F, Chan N, Bristow RG. A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother Oncol. 2008 Aug;88(2):258-68. Epub 2008 May 2. PubMed PMID: 18456354.

21: Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37. PubMed PMID: 17473206.