Olaparib (AZD2281, Ku-0059436)

Catalog No.S1060

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. Phase 3.

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Olaparib (AZD2281, Ku-0059436) Chemical Structure

Olaparib (AZD2281, Ku-0059436) Chemical Structure
Molecular Weight: 434.46

Validation & Quality Control

Cited by 75 publications:

13 customer reviews :

Quality Control & MSDS

Related Compound Libraries

Olaparib (AZD2281, Ku-0059436) is available in the following compound libraries:

PARP Inhibitors with Unique Features

  • Selective PARP Inhibitors

    AG-14361 PARP1-selective, Ki<5 nM. UPF 1069 PARP2-selective, IC50=0.3 μM.

  • Most Potent PARP Inhibitor

    MK-4827 (Niraparib) PARP1, IC50=3.8 nM; PARP2, IC50=2.1 nM.

  • PARP Inhibitor in Clinical Trial

    Iniparib (BSI-201) Phase III for solid tumors.

  • Newest PARP Inhibitor

    BMN 673 Novel PARP inhibitor with IC50 of 0.58 nM. Also a potent inhibitor of PARP-2, but does not inhibit PARG and highly sensitive to PTEN mutation. Novel PARP inhibitor with IC50

Product Information

  • Compare PARP Inhibitors
    Compare PARP Products
  • Research Area
  • Inhibition Profile
  • Olaparib (AZD2281, Ku-0059436) Mechanism

Product Description

Biological Activity

Description 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. Phase 3.
Targets PARP2 [1]
(Cell-free assay)
PARP1 [1]
(Cell-free assay)
Tankyrase-1 [1]
(Cell-free assay)
IC50 1 nM 5 nM 1.5 μM
In vitro Olaparib would act against BRCA1 or BRCA2 mutations. Olaparib is not sensitive to tankyrase-1 (IC50 >1 μM). Olaparib could ablate the PARP-1 activity at concentrations of 30-100 nM in SW620 cells. Olaparib is hypersensitive to BRCA1-deficient cell lines (MDA-MB-463 and HCC1937), compared with BRCA1- and BRCA2-proficient cell lines (Hs578T, MDA-MB-231, and T47D). [1] Olaparib is strongly sensitive to KB2P cells due to suppression of base excision repair by PARP inhibition, which may result in the conversion of single-strand breaks to double-strand breaks during DNA replication, thus activating BRCA2-dependent recombination pathways. [2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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Mouse H2AX−/− ES CellsNHnpSGxEgXSxdH;4bYMhSXO|YYm=MYOyMlUh|ryPM3mxT|IxKGh?NX6wRow5W2mpbnnmbYNidnSueTDpcohq[mm2czDj[YxtKHO3co\peoFtNYHWbGw5OjN|NUW0PFk>
Mouse ATM−/− ES CellsNXrWO|NiS3m2b4TvfIlkKEG|c3H5NEXtXowzNjVizszNM{G2O|IxKGh?M{KwdXNq\26rZnnjZY51dHliaX7obYJqfHNiY3XscEB{fXK4aY\hcC=>NELQSYEzOzN3NUS4PS=>
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MFM-223MkXOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?Ml7vTWM2OD12ND6xNlI5KM7:TR?=NWr0XIl6W0GQR1XS
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A101DNIW3SFhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MYjJR|UxRTR5Lk[zOVch|ryPM2OySHNCVkeHUh?=
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... Click to View More Cell Line Experimental Data

In vivo Combining with temozolomide, Olaparib (10 mg/kg, p.o.) significantly suppresses tumor growth in SW620 xenografts. [1] Olaparib shows great response to Brca1-/-;p53-/- mammary tumors (50 mg/kg i.p. per day), while no responses to HR-deficient Ecad-/-;p53-/- mammary tumors. Olaparib even does not show dose-limiting toxicity in tumor-bearing mice. [3] Olaparib has been used to treat with BRCA mutated tumors, such as ovarian, breast and prostate cancers. Moreover, Olaparib shows selectively inhibition to ATM (Ataxia Telangiectasia Mutated)-deficient tumor cells, which indicates to be a potential agent for treating ATM mutant lymphoid tumors. [4]
Features A potent PARP inhibitor (currently in late stage clinical trials).

Protocol(Only for Reference)

Kinase Assay:

[1]

FlashPlate assay (96-well screening assay) To columns 1 through 10, 1 μL of Olaparib (in DMSO) is added, and 1 μL DMSO only is added to the positive (POS) and negative (NEG) control wells (columns 11 and 12, respectively) of a pretreated FlashPlate. PARP-1 is diluted 1:40 in buffer (buffer B: 10% glycerol (v/v), 25 mM HEPES, 12.5 mM MgCl2,50 mM KCl, 1 mM DTT, 0.01% NP-40 (v/v), pH 7.6) and 40 μL added to all 96 wells (final PARP-1 concentration in the assay is ~1 ng/μL). The plate is sealed and shaken at RT for 15 min. Following this, 10 μL of positive reaction mix (0.2 ng/μL of double-stranded oligonucleotide [M3/M4] DNA per well, 5 μM of NAD+ final assay concentration, and 0.075 μCi 3H-NAD+ per well) is added to the appropriate wells (columns 1-11). The negative reaction mix, lacking the DNA oligonucleotide, is added to column 12 (with the mean negative control value used as the background). The plate is resealed and shaken for a further 60 min at RT to allow the reaction to continue. Then, 50 μL of ice-cold acetic acid (30%) is added to each well to stop the reaction, and the plate is sealed and shaken for a further 60 min at RT. Tritiated signal bound to the FlashPlate is then determined in counts per minute (CPM) using the TopCount plate reader.
In vitro isolated enzyme assay PARP-2 activity inhibition uses a variation of the PARP-1 assay in which PARP-2 protein (recombinant) is bound down by a PARP-2 specific antibody in a 96-well white-walled plate. PARP-2 activity is measured following 3H-NAD+ DNA additions. After washing, scintillant is added to measure 3H-incorporated ribosylations.

Cell Assay:

[1]

Cell lines Breast cancer cell lines including SW620 colon, A2780 ovarian, HCC1937, Hs578T, MDA-MB-231, MDA-MB-436, and T47D
Concentrations 1-300 nM
Incubation Time 7-14 days
Method

The cytotoxicity of Olaparib is measured by clonogenic assay. Olaparib is dissolved in DMSO and diluted by culture media before use. The cells are seeded in six well plates and left to attach overnight. Then Olaparib is added at various concentrations and the cells are incubated for 7-14 days. After that the surviving colonies are counted for calculating the IC50.

Animal Study:

[3]

Animal Models Brca1-/-;p53-/- mammary tumors are generated in K14cre;Brca1F/F;p53F/F mice.
Formulation 50 mg/mL stocks in DMSO with 10% 2-hydroxyl-propyl-β-cyclodextrine/PBS
Dosages 50 mg/kg
Administration Administered via i.p. injection at 10 μL/g of body weight

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Menear KA, et al. J Med Chem, 2008, 51(20), 6581-6591.

[2] Evers B, et al, Clin Cancer Res, 2008, 14(12), 3916-3925.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02546661 Not yet recruiting Muscle Invasive Bladder Cancer AstraZeneca August 2016 Phase 1
NCT02822157 Not yet recruiting Ovarian Epithelial Cancer Universitaire Ziekenhuizen Leuven|AstraZeneca August 2016 Phase 2
NCT02810743 Not yet recruiting Breast Cancer The Netherlands Cancer Institute August 2016 Phase 3
NCT02489006 Not yet recruiting Ovarian Cancer|Fallopian Tube Cancer|Neoadjuvant Treatment|Debulking Surgical Procedures University Health Network, Toronto July 2016 Phase 2
NCT02392676 Withdrawn Platinum Sensitive Relapsed Ovarian Cancer AstraZeneca|Myriad Genetic Laboratories, Inc. July 2016 Phase 3

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Chemical Information

Download Olaparib (AZD2281, Ku-0059436) SDF
Molecular Weight (MW) 434.46
Formula

C24H23FN4O3

CAS No. 763113-22-0
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 86 mg/mL warming (197.94 mM)
Water 0.002 mg/mL (0.0 mM)
Ethanol <1 mg/mL
In vivo 4% DMSO+30% PEG 300+ddH2O 5mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

Frequently Asked Questions

  • Question 1
    How long can the chemical compound be stable in DMEM at 4 ℃?

    Answer: The compound is stable in DMEM at 4 degree for one week.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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