subject: Azd2281 Is A New Menber In Parp Inhibitor [print this page] PARP INHIBITION AND AZD2281: PARP INHIBITION AND AZD2281:
As many disease conditions are more dependent on PARP enzymes, the targeting of PARP and its inhibition becomes an attractive approach for treating those conditions and cancer is one such example where this approach has been tested successfully. Most of these inhibitors are developed to spare the normal cells which do not often go for DNA replication while killing cancer cells where the deficiency of genes associated with DNA repair enzymes leaves them vulnerable to PARP inhibitors induced apoptosis.
AZD2281 PARP inhibitor is manufactured and developed by KuDOS Pharmaceuticals and AZD2281 IC50 for an effective PARP-1 and PARP-2 inhibition is 5 and 1 nM, respectively. Also available under the trade name of Olaparib from AZD2281 suppliers, one can buy AZD2281 for research and laboratory uses at AZD2281 prices of around $90 for a 25 mg package. AZD2281 solubility can be achieved in DMSO to give a 33 mg/ml solution. AZD2281 structure shows the presence of fluorine and a phthalazine group.
BIOLOGICAL ACTIVITIES OF AZD2281:
Various PARP inhibitors are tested for their efficacy against ovarian cancer [1] and breast cancer. Seeing those results, AZD2281 was used in breast cancer clinical trials where it reported remarkable results in inducing apoptosis in these cells [2] and the initial success led to an extensive study of AZD2281 for its therapeutic use [3]. AZD2281 was recommended as a synthetic lethal approach for genetically profiled patients to assess its efficacy in them [4]. AZD2281 mechanism was thought to induce apoptosis in cancer cells carrying USP11 mutation [5]. A significant decrease in proliferation and increase in apoptosis in ovarian cancer xenografts derived from BRCA mutation carrying patients established its reputation of being an antineoplastic PARP inhibitor [6]. The study of its safe dose, efficaciousness and pharmacokinetics showed that it is very effective as a part of combination therapy and was soon used with platinum drugs [7], Carboplatin [8] and Cisplatin [9] to produce synergistic apoptosis in rat models of mammary tumors. In case of lymphoid tumors with ATM deficiency, AZD2281 showed promising results [10]. AZD2281 also increases lung tumor xenografts sensitivity to radiotherapy [11].
SUMMARY OF TRIAL RESULTS ON AZD2281:
AZD2281 clinical trial showed its remarkable potential in treating patients carrying BRCA mutations [12] and phase I [13] and phase II [14-15] clinical trials were soon conducted in such patients affirming its efficacy. Its combination with Topotecan in patients with advanced solid tumors enrolled in a phase I trial [16] showed promise and the first PARP inhibitor AZD2281 was used with Dacarbazine too in similar conditions [17]. A phase I clinical study assessed its pharmacokinetics in breast cancer patients [18] but the success of AZD2281 in ovarian cancer patients reached a new high as they reported remarkable efficacy in phase I trials in ovarian cancer patients on platinum drugs [19] and these results were validated in phase II studies in advanced ovarian cancer patients too [20] warranting its approval for the treatment of breast and ovarian cancer. It was much successful on patients with triple negative breast cancer and high-grade advanced serous or undifferentiated ovarian tumors [21].
1. Banerjee, S.e.a., Making the best of PARP inhibitors in ovarian cancer. Nature Reviews Clinical Oncology, 2010. 7: p. 508-519.
2. Drew, Y.a.P., R., The emerging potential of poly(ADP-ribose) polymerase inhibitors in the treatment of breast cancer. Current Opinion in Obstetrics & Gynecology, 2010. 22(1): p. 67-71.
3. Menear, K.A.e.a., 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem, 2008. 51(20): p. 6581-91.
4. Tuma, R.S.e.a., Combining Carefully Selected Drug, Patient Genetics May Lead to Total Tumor Death. J Natl Cancer Inst, 2007. 99(20): p. 1505-1509.
5. Wiltshire, T.D.e.a., Sensitivity to Poly(ADP-ribose) Polymerase (PARP) Inhibition Identifies Ubiquitin-specific Peptidase 11 (USP11) as a Regulator of DNA Double-strand Break Repair. The Journal of Biological Chemistry, 2010. 285: p. 14565-14571.
6. Kortmann, U.e.a., Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts. Clin Cancer Res, 2011.
7. Rottenberg, S.e.a., 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): p. 17079-84.
8. Hay, T.e.a., Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res, 2009. 69(9): p. 3850-5.
9. Evers, B.e.a., Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin. Clin Cancer Res, 2008. 14: p. 3916.
10. Weston, V.J.e.a., The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood, 2010. 116(22): p. 4578-4587.
11. Senra, J.M.e.a., Inhibition of PARP-1 by Olaparib (AZD2281) Increases the Radiosensitivity of a Lung Tumor Xenograft. Mol Cancer Ther, 2011. 10: p. 1949.
12. Hutchinson, L.e.a., Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nature Reviews Clinical Oncology, 2010. 7(549).
13. Fong, P.C.e.a., Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. N Engl J Med, 2009. 361: p. 123-134.
14. Audeh, M.W.e.a., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. The Lancet, 2010. 376(9737): p. 245-251.
15. Tutt, A.e.a., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet, 2010. 376(9737): p. 235-244.
16. Samol, J.e.a., 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. Khan, O.A.e.a., A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumors. Br J Cancer, 2011. 104(5): p. 750-5.
18. Fong, P.C.e.a., Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med, 2009. 361(2): p. 123-34.
19. Fong, P.C.e.a., Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval. Journal of Clinical Oncology, 2010. 28(15): p. 2512-2519.
20. Audeh, M.W.e.a., Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol, 2009. 27(15S): p. 5500.
21. Gelmon, K.A.e.a., Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. The Lancet, 2011.
