Introduction: Mechanism of Action of Poly (ADP-ribose) polymerase (PARP)

Within any cellular growth process there must be facilities for the replication of DNA, however, this process is not always 100% accurate. In addition mechanisms for the repair of incorrect sequences or the repair of cytotoxic damaged DNA must exist in tandem. PARP is not part of a repair mechanism but it does function as one of the regulatory enzymes controlling the mechanisms that do repair DNA such as the BER/SSER pathway [1]. As well as regulating DNA repair PARP is a true multi-tasking protein since it also regulates the normal processes of cell disposal (ie cell death, apoptosis), development of neuro-functions and many other cell proliferation processes. PARP is typically located in the cell nucleus where in combination with other proteins recognizes minor DNA strand damage, forms skeletal structures around the site of the damage and enrolls specific proteins to remove the damaged section and replace the missing part [2;3].

With 17 known members of the PARP family, knowledge of the mechanism of action for PARP’s activity is essential for understanding its effect in diseased states [4-7]. PARP is an enzymatic protein that consists of four distinct sections each specific for the required task. PARP has a caspase cleavage domain for regulatory control of the caspase cascade in apoptotic pathways, a catalytic domain for the regulations of growth / proliferation kinases and two domains containing zinc (zinc fingers) for the recognition of DNA strand breaks [8-10]. PARP utilizes the energy protein NAD for its function and highly dependent on this energy to process correctly [11]. For chemotherapeutic action inhibiting the DNA binding domains or inhibiting the regulation of the caspase cascade are two attractive means of initiating changes in the transcription of DNA or the inducement of programmed cell death.

In terms of oncological action, research has established that both breast cancer and ovarian cancer have subpopulations [12-14], which have a mutation in the genes describing BCRA function. PARP has been linked with the activity of two of the BRCA proteins (1 & 2) and tumor down regulation which stimulates the uncontrolled growth associated with cancer [15]. The development of inhibitors for PARP is well advance with several compounds at the phase II and III level demonstrating the effectiveness of this approach [7;16;17].

The PARP inhibitor mechanism operates on the principle of the binding of the small molecule to PARP´s active domains. Competitive processes for NAD+ induces a decrease in PARP activity, inhibiting PARP will increase the number of DNA strand errors within a cell which leads to apoptosis. Cells with BRCA mutations are particularly vulnerable to this form of attck. Commercial sources for small molecules have developed PARP specific inhibitors with action against PARP 1 or PARP 1&2 that have been tested in preclinical studies. Examples of  PARP 1 selective inhibitors are Rucaparib, Ino 1001, AG14362 and A966492, while examples of PARP 1&2 inhibitor drugs are Olaparib, Veliparib and MK-4827 [18]. Researchers can buy PARP inhibitors from a variety of sources but prices vary greatly. PARP inhibition can be determined using specific PARP activity assay and PARP inhibitor assays that are freely available commercially.

Preclinical Experience:

PARP antagonists in oncology have been associated with two forms of pre-clinical activity; as single agents or in synergistic combinations and as a sensitizer for radiotherapy [19-23]. As single agents PARP agonists are effective against cells already possessing one or more mutations in DNA repair mechanisms. For example PARP inhibitors in breast cancer cell lines that are deficient in BCRA1 or 2 show a greater potency that in tumor cells of normal BCRA expression [24-26]. However, BCRA is not the only mechanism which shows mutations that increase sensitivity to PARP inhibitors, activity is seen in cell lines with PTEN mutations [27;28], PALB2 mutations [29;30] and ATM deficiencies [31;32]. Correlation of PARP 1 & 2 activity and expression in a panel of cell lines demonstrates that PARP1 is frequently over expressed in proteins and mRNA .

Clinical Status:

There are multiple PARP inhibitors in clinical trials being tested at phase 1 and phase II levels, the most significant of these was Olaparib by AstraZenica. However, poor phase II results have led to this molecule being dropped with reference to ovarian cancer [33]. Still at the last count seventeen clinical trials are being conducted for 5 different molecules at phase I and II. While results have not been released yet, this chemotherapeutic approach is still encouraging.



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S1098 Rucaparib (AG-014699) phosphate Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with Ki of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3. (105) (8)
S1132 3-Aminobenzamide 3-Aminobenzamide (3-ABA , 3-Amino Benzamide, 3-AB) is a potent inhibitor of Poly(ADP-ribose)polymerase (PARP) and inhibits cell apoptosis after SCI (Spinal Cord Injury) in caspase-independent way. (4) (2)

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