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PARP INHIBITOR IN CANCER, STROKE AND ISCHEMIA

by Selleckchem | Mar 18 2012

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.

References

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2. Liang Y, Lin SY et al. DNA damage response pathways in tumor suppression and cancer treatment. World J Surg 2009; 33(4):661-666.

3. Guo GS, Zhang FM et al. DNA repair and synthetic lethality. Int J Oral Sci 2011; 3(4):176-179.

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

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

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

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8. Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med 2005; 7(4):1-20.

9. Sharif R, Thomas P et al. The role of zinc in genomic stability. Mutat Res 2011.

10. Soldatenkov VA, Potaman VN. DNA-binding properties of poly(ADP-ribose) polymerase: a target for anticancer therapy. Curr Drug Targets 2004; 5(4):357-365.

11. Kun E, Bauer PI. Cell biological functions of PARP I: an overview. Ital J Biochem 2001; 50(1-2):15-18.

12. Weil MK, Chen AP. PARP inhibitor treatment in ovarian and breast cancer. Curr Probl Cancer 2011; 35(1):7-50.

13. Telli ML, Ford JM. PARP inhibitors in breast cancer. Clin Adv Hematol Oncol 2010; 8(9):629-635.

14. Rios J, Puhalla S. PARP inhibitors in breast cancer: BRCA and beyond. Oncology (Williston Park) 2011; 25(11):1014-1025.

15. Aly A, Ganesan S. BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. J Mol Cell Biol 2011; 3(1):66-74.

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

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

18. Underhill C, Toulmonde M et al. A review of PARP inhibitors: from bench to bedside. Ann Oncol 2011; 22(2):268-279.

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

20. Sanchez-Munoz A, Perez-Ruiz E et al. Targeted therapy of metastatic breast cancer. Clin Transl Oncol 2009; 11(10):643-650.

21. Soldatenkov VA, Smulson M. Poly(ADP-ribose) polymerase in DNA damage-response pathway: implications for radiation oncology. Int J Cancer 2000; 90(2):59-67.

22. Verheij M, Vens C et al. Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective. Drug Resist Updat 2010; 13(1-2):29-43.

23. Vesprini D, Narod SA et al. The therapeutic ratio is preserved for radiotherapy or cisplatin treatment in BRCA2-mutated prostate cancers. Can Urol Assoc J 2011; 5(2):E31-E35.

24. Wang W, Figg WD. Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance. Cancer Biol Ther 2008; 7(7):1004-1005.

25. Sledge GW, Jr., Jotwani AC et al. Targeted therapies in early-stage breast cancer: achievements and promises. Surg Oncol Clin N Am 2010; 19(3):669-679.

26. Drew Y, Plummer R. The emerging potential of poly(ADP-ribose) polymerase inhibitors in the treatment of breast cancer. Curr Opin Obstet Gynecol 2010; 22(1):67-71.

27. Amir E, Seruga B et al. Targeting DNA repair in breast cancer: a clinical and translational update. Cancer Treat Rev 2010; 36(7):557-565.

28. Heitz F, Harter P et al. Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy. Expert Rev Anticancer Ther 2010; 10(7):1125-1136.

29. Hellebrand H, Sutter C et al. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum Mutat 2011; 32(6):E2176-E2188.

30. Buisson R, Dion-Cote AM et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 2010; 17(10):1247-1254.

31. Yoon JH, Ahn SG et al. Role of autophagy in chemoresistance: Regulation of the ATM-mediated DNA-damage signaling pathway through activation of DNA-PKcs and PARP-1. Biochem Pharmacol 2011.

32. Smith J, Tho LM et al. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 2010; 108:73-112.

33. Kaye SB, Lubinski J et al. Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. J Clin Oncol 2011.

Cat.No.	Product Name	Information
S1098	Rucaparib phosphate	Rucaparib phosphate is an inhibitor of PARP with K_i of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3.
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.
S2197	A-966492	A-966492 is a novel and potent inhibitor of PARP1 and PARP2 with K_i of 1 nM and 1.5 nM, respectively.