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.


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Related Products

Cat.No. Product Name Information
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.

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