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MK-4827 hydrochloride

PARP1/PARP2 inhibitor CAS# 1038915-64-8

MK-4827 hydrochloride

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Chemical structure

MK-4827 hydrochloride

3D structure

Chemical Properties of MK-4827 hydrochloride

Cas No. 1038915-64-8 SDF Download SDF
PubChem ID 44550597 Appearance Powder
Formula C19H21ClN4O M.Wt 356.85
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Niraparib hydrochloride
Solubility DMSO : 250 mg/mL (700.57 mM; Need ultrasonic)
Chemical Name 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide;hydrochloride
SMILES C1CC(CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N.Cl
Standard InChIKey YXYDNYFWAFBCAN-PFEQFJNWSA-N
Standard InChI InChI=1S/C19H20N4O.ClH/c20-19(24)17-5-1-3-15-12-23(22-18(15)17)16-8-6-13(7-9-16)14-4-2-10-21-11-14;/h1,3,5-9,12,14,21H,2,4,10-11H2,(H2,20,24);1H/t14-;/m1./s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MK-4827 hydrochloride

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

References:
[1]. Jones P, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85. [2]. Bridges KA, et al. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget. 2014 Jul 15;5(13):5076-86. [3]. Wang L, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.

Protocol

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].

Cell Assay [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].

Animal Administration [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.

References:
[1]. Jones P, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85. [2]. Bridges KA, et al. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget. 2014 Jul 15;5(13):5076-86. [3]. Wang L, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.

MK-4827 hydrochloride Dilution Calculator

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MK-4827 hydrochloride Molarity Calculator

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Preparing Stock Solutions of MK-4827 hydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.8023 mL 14.0115 mL 28.023 mL 56.046 mL 70.0574 mL
5 mM 0.5605 mL 2.8023 mL 5.6046 mL 11.2092 mL 14.0115 mL
10 mM 0.2802 mL 1.4011 mL 2.8023 mL 5.6046 mL 7.0057 mL
50 mM 0.056 mL 0.2802 mL 0.5605 mL 1.1209 mL 1.4011 mL
100 mM 0.028 mL 0.1401 mL 0.2802 mL 0.5605 mL 0.7006 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on MK-4827 hydrochloride

MK-4827(Niraparib) Hcl is a selective inhibitor of PARP1/PARP2 with IC50 of 3.8 nM/2.1 nM; with great activity in cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP and Tank1.

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References on MK-4827 hydrochloride

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.[Pubmed:28001384]

J Med Chem. 2017 Feb 23;60(4):1262-1271.

Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

Description

Niraparib hydrochloride (MK-4827 hydrochloride) is a highly potent and orally bioavailable PARP1 and PARP2 inhibitor with IC50s of 3.8 and 2.1 nM, respectively. Niraparib hydrochloride leads to inhibition of repair of DNA damage, activates apoptosis and shows anti-tumor activity.

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