Niraparib (MK-4827)

Catalog No.S2741 Batch:S274103

Technical Data

Formula	C₁₉H₂₀N₄O
Molecular Weight	320.39	CAS No.	1038915-60-4
Solubility (25°C)*	In vitro	DMSO	64 mg/mL (199.75 mM)
		Ethanol	64 mg/mL (199.75 mM)
		Water	Insoluble
* <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. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

Niraparib (MK-4827) is a selective inhibitor of PARP1/2 with IC50 of 3.8 nM/2.1 nM, with great activity in cancer cells with mutant BRCA-1 and BRCA-2. It is >330-fold selective against PARP3, V-PARP and Tank1. Niraparib can form PARP–DNA complexes resulting in DNA damage, apoptosis, and cell death. Phase 3.

Targets

PARP2 ^[1] (Cell-free assay)	PARP1 ^[1] (Cell-free assay)
2.1 nM	3.8 nM

In vitro

In a whole cell assay, MK-4827 inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. It was demonstrated to be a potent and selective PARP-1 and PARP-2 inhibitor with IC50=3.8 and 2.1 nM, respectively. Furthermore, it displayed at least a 100-fold selectivity over PARP-3, V-PARP, and tankyrase-1, with IC50 = 1300, 330, and 570 nM, respectively. As well as inhibiting the growth of HeLa cell lacking BRCA-1 because of silencing by RNA interference, MK-4827 is able to inhibit the proliferation of cancer cell lines carrying natural BRCA-1 or BRCA-2 mutations. In MDA-MB-436 human mammary gland adenocarcinoma cells carrying BRCA-1 mutations, MK-4827 displayed CC50 = 18 nM, while in CAPAN-1 human pancreatic adenocarcinoma cells, which are BRCA-2 mutant, MK-4827 displayed CC50 = 90 nM. In contrast, normal human prostate and mammary epithelial cells are resistant to MK-4827, displaying antiproliferative effects in the micromolar range, thereby demonstrating the very high selective cytotoxicity from these PARP inhibitors in BRCA-1 and -2 mutant cancer cells compared to surrounding tissue^[2].

In vivo

MK-4827, a novel, orally bioavailable, PARP-1 and PARP-2 inhibitor, strongly enhanced the effect of radiation on a variety of human tumor xenografts, both p53 wild type and p53 mutant^[1]. It was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer^[2].

Protocol (from reference)

Cell Assay:^{^[2]}	Cell lines HeLa BRCA1-silenced cells Concentrations serial dilutions Incubation Time 7 days Method Proliferation assays were conducted in 96-well black viewplates, and 300 cells/well (250 cell/well for BRCA-1 wt) in culture medium, 190 μL/well (DMEM containing 10% FCS, 0.1 mg/mL penicillin-streptomycin, and 2 mM L-glutamine), were plated and incubated for 4 h at 37℃ under 5% CO2 atmosphere. Inhibitors were then added with serial dilutions, 10 μL/well to obtain the desired final compound concentration in 0.5% DMSO. The cells were then incubated for 7 days at 37℃ in 5% CO2 after which time viability was assessed. Briefly, with CellTiter-Blue solution prediluted 1:10 in medium, 100 μL/well was added and the cells left for 45 min at 37℃ under 5% CO2 and then a further 15 min at room temperature in the dark. The number of living cells was determined by reading the plate at fluorimeter, excitation at 550 nm and emission at 590 nm. Cell growth was expressed as the percentage growth with respect to vehicle treated cells. The concentration required to inhibit cell growth by 50% (CC50) was determined.
Animal Study:^{^[1]}	Animal Models Female nude mice Dosages 25 mg/kg twice daily or 50 mg/kg once daily Administration oral administration

Cell Assay:^{^[2]}

Cell lines
HeLa BRCA1-silenced cells
Concentrations
serial dilutions
Incubation Time
7 days
Method
Proliferation assays were conducted in 96-well black viewplates, and 300 cells/well (250 cell/well for BRCA-1 wt) in culture medium, 190 μL/well (DMEM containing 10% FCS, 0.1 mg/mL penicillin-streptomycin, and 2 mM L-glutamine), were plated and incubated for 4 h at 37℃ under 5% CO2 atmosphere. Inhibitors were then added with serial dilutions, 10 μL/well to obtain the desired final compound concentration in 0.5% DMSO. The cells were then incubated for 7 days at 37℃ in 5% CO2 after which time viability was assessed. Briefly, with CellTiter-Blue solution prediluted 1:10 in medium, 100 μL/well was added and the cells left for 45 min at 37℃ under 5% CO2 and then a further 15 min at room temperature in the dark. The number of living cells was determined by reading the plate at fluorimeter, excitation at 550 nm and emission at 590 nm. Cell growth was expressed as the percentage growth with respect to vehicle treated cells. The concentration required to inhibit cell growth by 50% (CC50) was determined.

Animal Study:^{^[1]}

Animal Models
Female nude mice
Dosages
25 mg/kg twice daily or 50 mg/kg once daily
Administration
oral administration

References

Customer Product Validation

: Data from [Oncogene, 2013, 32(47):5377-87]

: Data from [Data independently produced by , , Theranostics, 2017, 7(17):4340-4349]

: Data from [Data independently produced by , , Cancer Lett, 2018, 432:84-92]

: Data from [Data independently produced by , , Cell Death Dis, 2017, 8(10):e3070]

Selleck's Niraparib (MK-4827) has been cited by 96 publications

Base editing screens define the genetic landscape of cancer drug resistance mechanisms [ Nat Genet, 2024, 10.1038/s41588-024-01948-8]	PubMed: 39424923
PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response [ EBioMedicine, 2024, 103:105129]	PubMed: 38640836
Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos [ Cell Death Discov, 2024, 10(1):74]	PubMed: 38346947
Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro [ Int J Mol Sci, 2024, 25(2)886]	PubMed: 38255960
Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib [ Int J Mol Sci, 2024, 25(11)5629]	PubMed: 38891817
Exosomal miR-664a-5p as a therapeutic target biomarker for PARP inhibitor response in prostate cancer [ Am J Cancer Res, 2024, 14(8):3789-3799]	PubMed: 39267686
Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma [ Cancers (Basel), 2024, 16(16)2852]	PubMed: 39199623
177Lu-SN201 nanoparticle shows superior anti-tumor efficacy over conventional cancer drugs in 4T1 orthotopic model [ Invest New Drugs, 2024, 42(4):471-477.]	PubMed: 38837077
USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity [ Sci Adv, 2024, 10(46):eadp6567]	PubMed: 39536107
Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines [ Cancer Res Commun, 2024, ]	PubMed: 39485057

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