Niraparib tosylate inhibits PARP1/PARP2 with IC50 of 3.8 nM/2.1 nM respectively. 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 is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. 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.
|Cell lines||V-C8 cells|
|Preparation method||V-C8 (BRCA2-negative) Chinese hamster cells are treated with the PARP inhibitor MK-4827 for 24 h, washed and incubated in drug-free medium for 5-7 days until colonies formed.|
|Incubation time||24 h|
|Animal models||Female nude mice (Ncr Nu/Nu)|
|Formulation||Suspended in 0.5% Methocel in deionized water|
|Dosages||25 or 50 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO: ≥ 60 mg/mL|
Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells.
Bridges KA, et al. Oncotarget. 2014 Jul 15;5(13):5076-86. PMID: 24970803.
Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma.
Mueller S, et al. Anticancer Res. 2013 Mar;33(3):755-62. PMID: 23482742.
Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes.
Patel AG, et al. J Biol Chem. 2012 Feb 3;287(6):4198-210. PMID: 22158865.
MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation.
Wang L, et al. Invest New Drugs. 2012 Dec;30(6):2113-20. PMID: 22127459.
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E7449 is an orally bioavailable, brain penetrable, small molecule dual inhibitor of PARP1/2 that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1/2), important regulators of canonical Wnt/β-catenin signaling. It has IC50 values of 1.0 and 1.2 nM for PARP1 and 2, respectively.
BMN-673 (8R,9S) is the (8R,9S) enantiomer of BMN-673.BMN673 is a potent inhibitor of poly (ADP-ribose) polymerases (PARP)-1 and -2.
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