1. Cell Cycle/DNA Damage
    Epigenetics
  2. PARP

MK-4827 (Synonyms: Niraparib)

Cat. No.: HY-10619 Purity: 99.39% ee.: 99.90%
Data Sheet SDS Handling Instructions

MK-4827 is an excellent PARP1 and PARP2 inhibitor with IC50 of 3.8 and 2.1 nM, respectively.

For research use only. We do not sell to patients.
MK-4827 Chemical Structure

MK-4827 Chemical Structure

CAS No. : 1038915-60-4

Size Price Stock Quantity
10 mM * 1 mL in DMSO $99 In-stock
5 mg $90 In-stock
10 mg $150 In-stock
50 mg $400 In-stock
100 mg $650 In-stock
200 mg   Get quote  
500 mg   Get quote  

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Description

MK-4827 is an excellent PARP1 and PARP2 inhibitor with IC50 of 3.8 and 2.1 nM, respectively.

IC50 & Target

IC50: 3.8 nM (PARP1), 2.1 nM (PARP2)[1]

In Vitro

MK-4827 (Niraparib) inhibits PARP activity with EC50=4 nM and EC90=45 nM in a whole cell assay. MK-4827 inhibits proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10−100 nM range. MK-4827 displays excellent PARP 1 and 2 inhibition with IC50=3.8 and 2.1 nM, respectively, and in a whole cell assay[1]. To validate that MK-4827 (Niraparib) inhibits PARP in these cell lines, A549 and H1299 cells are treated with 1 μM MK-4827 for various times and measured PARP enzymatic activity using a chemiluminescent assay. The results show that MK-4827 inhibits PARP within 15 minutes of treatment reaching about 85% inhibition in the A549 cells at 1 h and about 55% inhibition at 1 h for the H1299 cells[2].

In Vivo

MK-4827 is well tolerated and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. MK-4827 is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. MK-4827 is characterized by acceptable pharmacokinetics in rats with plasma clearance of 28 (mL/min)/kg, very high volume of distribution (Vdss=6.9 L/kg), long terminal half-life (t1/2=3.4 h), and excellent bioavailability, F=65%[1]. MK-4827 enhances radiation response of p53 mutant Calu-6 tumor in both cases, with the single daily dose of 50 mg/kg being more effective than 25 mg/kg given twice daily[3].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT01226901 Merck Sharp & Dohme Corp. Neoplasms|Solid Tumors November 2010 Phase 1
NCT01244009 Tesaro, Inc. Lymphoma|Mantle-Cell December 2010 Phase 2
NCT01227941 Tesaro, Inc. Ovarian Cancer November 2010 Phase 1
NCT00749502 Tesaro, Inc. Solid Tumors|Chronic Lymphocytic Leukemia|T-cell-prolymphocytic Leukemia September 2008 Phase 1
NCT01294735 Merck Sharp & Dohme Corp. Recurrence of Solid Tumor|Glioblastoma Multiforme|Melanoma February 2011 Phase 1
NCT01110603 Tesaro, Inc. Cancer: Solid Tumors July 2010 Phase 1
NCT03209401 Georgetown University|Thomas Jefferson University|Tesaro, Inc. Solid Tumor, Adult|Homologous Recombination Deficiency September 2017 Phase 1
NCT01847274 Tesaro, Inc.|European Network of Gynaecological Oncological Trial Groups (ENGOT)|Myriad Genetics, Inc.|US Oncology Research|Sarah Cannon|Cooperative Ovarian Cancer Group for Immunotherapy (COGI) Network|Facing Our Risk of Cancer Empowered Platinum Sensitive Ovarian Cancer June 2013 Phase 3
NCT03076203 Thomas Jefferson University|Janssen, LP|Prostate Cancer Clinical Trials Consortium|Bayer Prostate Carcinoma Metastatic to the Bone|Stage IV Prostate Adenocarcinoma|Hormone-refractory Prostate Cancer May 2017 Phase 1
NCT02826512 The Netherlands Cancer Institute|Tesaro, Inc. Breast Cancer August 2016 Phase 2
NCT02500901 Paul Mathew, MD|Hoosier Cancer Research Network|Tesaro, Inc. Metastatic Prostate Cancer March 2016 Phase 1
NCT02854436 Janssen Research & Development, LLC Prostatic Neoplasms August 31, 2016 Phase 2
NCT02354586 Tesaro, Inc.|Facing Our Risk of Cancer Empowered|Myriad Genetics, Inc. Ovarian Cancer March 2015 Phase 2
NCT03016338 University Health Network, Toronto|Tesaro, Inc. Endometrial Cancer March 2017 Phase 2
NCT02657889 Tesaro, Inc.|Merck Sharp & Dohme Corp. Triple Negative Breast Cancer|Ovarian Cancer|Breast Cancer|Metastatic Breast Cancer|Advanced Breast Cancer|Stage IV Breast Cancer|Fallopian Tube Cancer|Peritoneal Cancer March 2016 Phase 1|Phase 2
NCT02354131 Nordic Society for Gynaecologic Oncology|ENGOT|GCIG|University of Utah|Massachusetts General Hospital|Myriad Genetics, Inc. Ovarian Cancer February 2015 Phase 1|Phase 2
NCT03207347 University of Florida|Tesaro, Inc. Mesothelioma|Uveal Melanoma|Renal Cell Carcinoma|Cholangiocarcinoma September 2017 Phase 2
NCT01905592 Tesaro, Inc.|European Organisation for Research and Treatment of Cancer - EORTC|Breast International Group|Myriad Genetic Laboratories, Inc.|US Oncology Research|Sarah Cannon|Facing Our Risk of Cancer Empowered Carcinoma of Breast|Human Epidermal Growth Factor 2 Negative Carcinoma of Breast|BRCA1 Gene Mutation|BRCA2 Gene Mutation October 2013 Phase 3
NCT03154281 Avera McKennan Hospital & University Health Center Breast Cancer|Ovarian Cancer June 2017 Phase 1
NCT02476552 Tesaro, Inc. Cancer February 2015 Phase 1
NCT02655016 Tesaro, Inc.|Gynecologic Oncology Group|European Network of Gynaecological Oncological Trial Group (ENGOT)|Myriad Genetics, Inc. Ovarian Cancer April 2016 Phase 3
NCT02924766 Janssen Research & Development, LLC Prostatic Neoplasms October 3, 2016 Phase 1
NCT02044120 Sarcoma Alliance for Research through Collaboration Ewing Sarcoma May 2014 Phase 1
NCT03025867 Tesaro, Inc. Recurrent Ovarian Cancer
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 3.1212 mL 15.6060 mL 31.2120 mL
5 mM 0.6242 mL 3.1212 mL 6.2424 mL
10 mM 0.3121 mL 1.5606 mL 3.1212 mL
Kinase Assay
[1]

Enzyme assay is conducted in buffer containing 25 mM Tris, pH 8.0, 1 mM DTT, 1 mM spermine, 50 mM KCl, 0.01% Nonidet P-40, and 1 mM MgCl2. PARP reaction contains 0.1 μCi [3H]NAD+ (200 000 DPM), 1.5 μM NAD+, 150 nM biotinylated NAD+, 1 μg/mL activated calf thymus, and 1−5 nM PARP-1. Autoreactions utilizing SPA bead-based detection are carried out in 50 μL volumes in white 96-well plates. Compounds (e.g., MK-4827) are prepared in 11-point serial dilution in 96-well plate, 5 μL/well in 5% DMSO/H2O (10× concentrated). Reactions are initiated by adding first 35 μL of PARP-1 enzyme in buffer and incubating for 5 min at room temperature and then 10 μL of NAD+ and DNA substrate mixture. After 3 h at room temperature, these reactions are terminated by the addition of 50 μL of streptavidin-SPA beads (2.5 mg/mL in 200 mM EDTA, pH 8). After 5 min, they are counted using a TopCount microplate scintillation counter. IC50 data is determined from inhibition curves at various substrate concentrations[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[2]

MK-4827 (Niraparib) is dissolved in DMSO and stored, and then diluted with appropriate media before use[2].

The inhibition of PARP is analyzed in A549 and H1299 cells using the HT Universal Chemiluminescent PARP Assay Kit. Briefly, cells are treated with DMSO or 1 μM niraparib for 15, 30, 60, or 120 minutes, trypsinized, and transferred to a pre-chilled tube. The cells are washed twice with ice cold PBS and resuspended in cold PARP extraction buffer. The cell suspensions are incubated on ice for 30 minutes with periodic vortexing to disrupt the cell membrane. The suspensions are centrifuged and the supernatant transferred to a pre-chilled tube on ice. The histone coated wells of the 96-well plate are rehydrated with 1X PARP buffer and incubated at room temperature for 30 minutes. The PARP buffer is removed and 20 μg of protein as determined by the Bio-Rad Protein Assay is added to each well followed by diluted PARP-HSA enzyme and 1X PARP buffer. The strip wells are then incubated at room temperature for 60 minutes, washed twice with PBS containing 0.1% Triton X-100, and then washed with PBS. Diluted Strep-HRP is added to the strip wells and incubated for 60 minutes at room temperature. The wells are washed again as before. Equal volumes of PeroxyGlow A and B are combined and added to the wells and chemiluminescent readings are obtained immediately using a plate-reader[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[3]

MK-4827 is suspended in 0.5% Methocel in deionized water, mixed for 24 h (Mice)[3].

Mice[3]
Female nude mice (Ncr Nu/Nu) are randomly assigned to treatment groups consisting of 5 to 8 mice each when tumors grew to 6.0 mm in diameter at which time treatment with MK-4827 is initiated. MK-4827 is given at a dose of 25 mg/kg twice daily or 50 mg/kg once daily for either 21 days or is discontinued at 9 days from the time tumors reached 8 mm in diameter. Fractionated local tumor irradiation (XRT) is given when tumors reach 8.0 mm in diameter (7.7-8.2 mm). Radiation (2 Gy per fraction) is delivered to the tumor-bearing leg of mice once daily for 14 consecutive days or twice daily for 7 consecutive days using a small-animal irradiator consisting of two parallel-opposed 137Cs sources, at a dose rate of 5 Gy/min. During irradiation un-anesthetized mice are mechanically immobilized in a jig so that the tumor is centered within a 3.0 cm diameter radiation field and the animal’s body shielded from radiation exposure. On the day when both MK-4827 and radiation are given, drug is administered 1 h before the first radiation dose of the day. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
M.Wt

320.39

Formula

C₁₉H₂₀N₄O

CAS No.

1038915-60-4

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 32 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.39% ee.: 99.90%

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MK-4827
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