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OLAPARIB FOR PARP-1 INHIBITION

PARP-1 Inhibition and its Implications in Cancer:

The Poly [ADP-ribose] polymerase 1 or PARP-1 proteins have been well documented to be linked with cancers affecting their differentiation, proliferation and transformation [1]. On the other hand, BRCA1 and BRCA2 genes are also well linked with the highly proliferating ovarian and breast cancer [2] and hence the development of PARP-1 inhibitors that can target the aforementioned genes effectively in breast and ovarian cancer cells has been considered as a very attractive and feasible approach. The increasing popularity of PARP-1 inhibitors can be attributed to their specific action against cancer cells while sparing normal cells.

Introduction of Olaparib:

Olaparib PARP-1 inhibitor is manufactured by KuDOS Pharmaceuticals and developed as a drug against ovarian and breast cancer. Olaparib IC50 for an effective PARP-1 inhibition is 5 nm and for PARP-2 is 1 nM. Olaparib suppliers supply it under the trade name of AZD2281. Olaparib price is reasonable and one can buy Olaparib easily for laboratory uses for $90 for a 25 mg vial. Olaparib solubility is in DMSO. Olaparib structure shows the presence of phthalazine and fluorine groups.

Olaparib (AZD2281) Chemical Structure

Olaparib’s Inhibition of PARP-1:

Many PARP-1 inhibitors were successfully developed against ovarian cancer [4]. Due to the association of aberrations in PARP-1 pathways with breast cancer, many of these PARP-1 inhibitors were tested in Olaparib breast cancer studies [3]. There is a bioavailable form of Olaparib inhibitor too. Olaparib was used for treating many patients based on the ‘synthetic lethal approach’ adopted after genetic profiling of the patients. The USP11 mutation regulates the sensitivity of cancer cells towards Olaparib significantly [5].

Preclinical Assessment of Olaparib:

Many ovarian and breast cancer preclinical studies involving various in vitro and in vivo models assessed its pharmacokinetics effectively. Olaparib is very effective both as a single agent or as a part of combination therapy involving other drugs and some examples are its synergistic efficacy with Carboplatin [6], Cisplatin and platinum drugs in rat mammary tumors and other cancer types. Olaparib also enhances the sensitivity of lung cancer xenografts for advanced radiotherapy.

Olaparib in Imaging Studies:

Olaparib was modified extensively owing to its immense use in various imaging studies [7]. Olaparib structure has a fluorine molecule which was labeled for PET imaging to be used for a high-performance technique. Apart from this 18F labeling, some studies attached a florescent probe to Olaparib which aided in its visualization in different test conditions.

Olaparib at Clinical Levels:

Olaparib was found to be very effective in treatment resistant patients. Olaparib has been used in various phase I and phase II [8] clinical trials having patients harboring BRCA1 mutations. Olaparib’s combination with Topotecan was shown to be very efficacious against advanced solid tumors when tested in phase I studies. Similarly its combination with Dacarbazine generated good results in solid tumor patients enrolled in phase I studies. Olaparib ovarian cancer clinical trials were most successful than its breast cancer trials and it generated remarkable results in different phase I and II studies [9].

References:

1. Helleday, T. et al, Perspective Poly (ADP-Ribose) Polymerase (PARP-1) in Homologous Recombination and as a Target for Cancer Therapy. Cell Cycle, 2005.

2. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 1994.

3. Farmer, H. et al, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005.

4. Audeh, M.W. 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. The Lancet, 2010.

5. Wang, X.Z. et al, The ups and downs of DNA repair biomarkers for PARP inhibitor therapies. American Journal of Cancer Research, 2011.

6. Kortmann, U. et al, Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xenografts. Clin Cancer Res, 2011.

7. Reiner, T.e.a., Synthesis and In Vivo Imaging of a 18F-Labeled PARP1 Inhibitor Using a Chemically Orthogonal Scavenger-Assisted High-Performance Method. Angewandte Chemie International Edition, 2011.

8. 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.

9. Hutchinson, L. et al, Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nature Reviews Clinical Oncology, 2010.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
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. (844) (18)

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