Choose Your Country or Region

AZD2281: THE FIRST PARP INHIBITOR

by Selleckchem | Mar 13 2012

Introduction: PARP Inhibition

Poly (ADP-ribose) polymerase (PARP) is an enzyme located in the cell nucleus that regulates apoptosis and controls repair of minor damaged DNA strands. Since DNA mutations are a common function of many clinical diseases PARP is a significant target for chemotherapeutic action. With 17 known members of the PARP family the mechanism of action for PARP’s activity is important to understand [1-4]. The PARP protein consists of 4 important area’s; the Zinc figures where DNA repair takes place, a caspase cleavage function, a catalytic domain and a modification domain. Chemotherapeutic action is considered to be via the caspase domain or via the DNA repair domain. Inhibiting the repair of DNA strands triggers the automatic functions of cell death. Inhibitors for PARP have been developed and tested pre-clinically demonstrating the effectiveness of this approach [4-6].

Olaparib (AZD2281) Chemical Structure

AZD2281: Properties and Availability

The AZD2281 Aurora inhibitor is marketed by Astra Zenica after its acquisition KuDOS under the trade name of Olaparib but originally it was researched with the drug code KU-0059436. The AZD2281 structure is based on a phthalazine derivative. AZD2281 solubility in water is extremely poor but AZD2281 is soluble in DMSO and ethanol at a maximum concentrations of 33 mg/ml and 1.7 mg/ml respectively. AZD2281 stability is listed for its powdered free base and this can be stored for upwards of 2 years if kept at -20^oC or below. Researchers can buy AZD2281 free base from a variety of AZD2281 suppliers although AZD2281 cost is dependent on the supplier. AZD2281 price of a 25 mg vial can range from $115 up to $553; researchers are advised to shop very carefully for this product.

AZD2281: Preclinical Investigations

PARP inhibitors have shown activity in the treatment diseases related to hereditary DNA mutation such as the deficiency of BRAC in ovarian cancer and breast cancer. Initial investigations demonstrated that AZD2281 had a high degree of efficacy in breast cancer cells as well as ovarian. [7-11]. Based on the genetic differences on the cell lines that responded screening processes for phase I trials were recommended [12]. In addition to ovarian and breast cancer AZD2281 has been tested in xenographs of lung cancer [13;14], of solid tumors [15-17] and aggressive lymphoma [18]. In a study utilizing radioactivity against on non-Hodgkin's lymphoma cell lines AZD2281 was found to be highly-radio sensitizing promoting recommendations that this line of research is continued in a patient population [19].

AZD2281: Clinical Status

Two phase 1 trials were initiated with AZD2281 as “proof of concept” of PARP inhibition with PARP inhibitors. The patients were screened for BRAC1 and BRAC 2 mutations suffering from either advanced breast cancer or advanced ovarian cancer. Toxicities observed were low grade and within acceptable parameters while clinical efficacy was seen in 41% response was seen in breast cancer while 33% was seen in ovarian cancer [20;21]. Further AZD2281 clinical trials were conducted in advanced solid tumors in combination with dacarbazine or bevacizumab. Results from these two trials were reported and no real clinical benefits was seen in the dacarbazine combination for melanoma advanced tumors, while the bevacizumab combination was well tolerate but no response were reported [15;22]. As sole therapy in an asian population AZD2281 was found to be well tolerated and preliminary response was actually seen [17]. In a separate study in ovarian cancer patients with BRCA1/2-mutatation were treated with AZD2281. The results showed response in patients that correlated to platinum sensitivity similar to that observed in preclinical studies [10;13;23-26]. In December 2011 Astra Zenica made the official statement that in the phase II study in serious ovarian cancer the treatment was demonstrating a negative long term benefit. In view of this and failures to find a suitable dosing format the phase III studies were canceled and further development of Olaparib in serious ovarian cancer would be canceled.

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

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

7. 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.

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

9. 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.

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

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

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

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

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

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

26. 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.