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OLAPARIB: THE FIRST PARP INHIBITOR

Introduction: PARP Inhibition

Signaling activities within the cell are conducted along set pathways of protein – protein interactions. Depending on the cell status and the ligands triggering the signaling cascade to what function is carried out in the nucleus. A protein located in the nucleus has been established to be the principle regulator of the apoptosis and repair functions of certain DNA damage. This protein is called “Poly (ADP-ribose) polymerase” or it is abbreviated to “PARP”. The PARP family of proteins is extensive with 17 members currently known and the range of effects of PARP activity is large[1-4]. The general structure of the PARP series of proteins contains four different types of binding domains which dictate the activity, one of the domains is referred to as the catalytic domain contains an amino acid sequence that is identical between all the members of the protein family. The mechanism of action of PARP proteins is to add a series of ADP ribose molecules to the protein ligands, the number and site of this addition controls the response of the affected protein [5;6]. Since PARP proteins are involved in the repair of simple DNA strand breaks and other minor damage to DNA they represent a potential target for chemotherapeutic action. In this relatively new area of study one of the first PARP inhibitors is Olaparib and it is in both preclinical and clinical testing [4;7;8].

Olaparib (AZD2281) Chemical Structure

OLAPARIB: Properties and Availability

A biopharmaceutical company named Kudos Plc originally developed the Olaparib Aurora inhibitor but this company was acquired by the multinational pharmaceutical giant Astra Zenica who has continued to develop the drug. Based on a fluoride phthalazine the Olaparib structure is ideal for use as a PET imaging drug and several methodologies have been found to promote this idea [9;10]. The major problem with Olaparib is that despite being soluble in DMSO up to 33 mg/ml it is nearly insoluble in aqueous solutions hence drug administration on systemic transport remain an issue. It should also be noted that Olaparib solubility in ethanol, unlike many similar molecular structures, is to a maximum of 1.7 mg/ml. If kept at -20°C the Olaparib stability can be estimated with an expiration date of 2 years, although it may be longer and retesting of purity is advised. There are several Olaparib suppliers of the free base with adequate purity from which one can buy Olaparib for research purposes. However, the Olaparib cost is dependant of the source, for a 25 mg vial the Olaparib price can range from $115 up to $553 for the same purity.

OLAPARIB: Preclinical Investigations

Olaparib was originally known as KU-0059436 and AZD-2281 in published research literature. As such it was demonstrated that preclinical evidence of PARP inhibitors efficacy in a subset of Breast and Ovarian cancer tumors was relevant to Olaparib. Breast cancer cell lines were shown to undergo apoptotic events when treated with Olaparib with IC50’s in the low nM range. However, this activity was limited to cell lines that had genetic mutation, in the case of breast and ovarian cancer this was the BRAC deficient tumors [11-15]. With good efficacy being in vitro for both breast and ovarian cancer the phase 1 trials were initiated relatively quickly with FDA approval. These trials were one of the first to use patient genetic screening for the sole purpose of determining likely patient response [16]. In NSCLC xenographs activity of Olaparib again was limited to the mutated tumor strains but when limited to those cell lines demonstrated good activity [17;18]. In solid tumors and aggressive lymphoma tumor types Olaparib was shown to be activity in an anti- tumor manor [19-21] but not always effective [22]. Another use for this molecule was as a combination treatment in the radioactive therapy of non-Hogkins lymphoma cell lines where Olaparib was clearly demonstrated to be radio-sensitizing [23].

OLAPARIB: Clinical Status

The initial promise of Olaparib was pursued rapidly into phase I clinical trials with preselected patient group of both breast and ovarian tumors in an advanced state. Olaparib demonstrated significant results in both tumor types [24;25]. However, contradictory results have been reported in relation to phase II trials in ovarian cancer [14;17;26-29]. Olaparib Clinical trials demonstrated no response even when used in combination with bevacizumab or dacarbazine, completely at odds with the response seen in the phase I stage [19;30].. Another trial with an Asian sub population found Olaparib well tolerated and demonstrating good efficacy [21]. In view of these results and the developing data that long term treatment in ovarian cancer was less effective than standard first line therapy Astra Zenica announced cancelation of this drug with a loss of approximately 285 million dollars written off.

References

    1.    Annunziata CM, O'Shaughnessy J. Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer. Clin Cancer Res 2010; 16(18):4517-4526.

    2.    Masutani M, Nakagama H et al. Poly(ADP-ribose) and carcinogenesis. Genes Chromosomes Cancer 2003; 38(4):339-348.

    3.    Drew Y, Calvert H. The potential of PARP inhibitors in genetic breast and ovarian cancers. Ann N Y Acad Sci 2008; 1138:136-145.

    4.    Javle M, Curtin NJ. The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer 2011; 105(8):1114-1122.

    5.    Otto H, Reche PA et al. In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs). BMC Genomics 2005; 6:139.

    6.    Ame JC, Spenlehauer C et al. The PARP superfamily. Bioessays 2004; 26(8):882-893.

    7.    Irshad S, Ashworth A et al. Therapeutic potential of PARP inhibitors for metastatic breast cancer. Expert Rev Anticancer Ther 2011; 11(8):1243-1251.

    8.    Chen A. PARP inhibitors: its role in treatment of cancer. Chin J Cancer 2011; 30(7):463-471.

    9.    Reiner T, Keliher EJ et al. Synthesis and in vivo imaging of a 18F-labeled PARP1 inhibitor using a chemically orthogonal scavenger-assisted high-performance method. Angew Chem Int Ed Engl 2011; 50(8):1922-1925.

  10.    Keliher EJ, Reiner T et al. High-Yielding, Two-Step (18)F Labeling Strategy for (18)F-PARP1 Inhibitors. ChemMedChem 2011.

  11.    Kortmann U, McAlpine JN et al. Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xenografts. Clin Cancer Res 2011; 17(4):783-791.

  12.    Schmidt C. Ovarian cancer treatments on the horizon. J Natl Cancer Inst 2011; 103(17):1284-1285.

  13.    Fong PC, Boss DS et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2):123-134.

  14.    Martinek I, Haldar K et al. DNA-repair pathway inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev 2010;(6):CD007929.

  15.    Narod SA. BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 2010; 7(12):702-707.

  16.    Menear KA, Adcock C et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phth alazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 2008; 51(20):6581-6591.

  17.    Forster MD, Dedes KJ et al. Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer. Nat Rev Clin Oncol 2011; 8(5):302-306.

  18.    Senra JM, Telfer BA et al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther 2011; 10(10):1949-1958.

  19.    Dean E, Middleton MR et al. Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer 2012.

  20.    Samol J, Ranson M et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs 2011.

  21.    Yamamoto N, Nokihara H et al. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci 2011.

  22.    Schaefer NG, James E et al. Poly(ADP-ribose) polymerase inhibitors combined with external beam and radioimmunotherapy to treat aggressive lymphoma. Nucl Med Commun 2011; 32(11):1046-1051.

  23.    Telli ML. PARP inhibitors in cancer: moving beyond BRCA. Lancet Oncol 2011; 12(9):827-828.

  24.    Tutt A, Robson M et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010; 376(9737):235-244.

  25.    Audeh MW, Carmichael J et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010; 376(9737):245-251.

  26.    Fong PC, Yap TA et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010; 28(15):2512-2519.

  27.    Rottenberg S, Jaspers JE et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008; 105(44):17079-17084.

  28.    Sessa C. Update on PARP1 inhibitors in ovarian cancer. Ann Oncol 2011; 22 Suppl 8:viii72-viii76.

  29.    Takahashi M, Koi M et al. MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor. J Biol Chem 2011; 286(14):12157-12165.

  30.    Khan OA, Gore M et al. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer 2011; 104(5):750-755.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1060 Olaparib (AZD2281) Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations. (842) (18)

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