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MK-4827 is a novel, selective and orally bioavailable PARP1/PARP2 inhibitor with IC50 of 3.8 nM and 2.1 nM, respevctively.MK-4827 has shown great activity against cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP and Tank1 [1].
Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 belong to a family of enzymes (PARP) that, using β-NAD+as a substrate, catalyze poly(ADP-ribosyl)ation of proteins, synthesize and transfer ADP-ribose polymers onto glutamate, aspartate or lysine residues of acceptor proteins, modifying their functional properties. PARP inhibitors compete with NAD+ at the highly conserved enzyme active site, making them new potential therapeutic strategies as chemo- and radio-potentiation and for the treatment of cancers with specific DNA repair defects as single-agent therapies [2].
In vitro: MK-4827displayed excellent PARP 1 and 2 inhibition with IC50 of 3.8 and 2.1 nM, respectively. In a whole cell assay, MK-4827 inhibited PARP activity with EC50 of 4 nM. MK-4827 also inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range[1].
In vivo: In a variety of human tumor xenografts of differing p53 status,MK-4827 showed high potential to improve the efficacy of radiotherapy,such as Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma [3].
References:[1] Jones P1,Altamura S,Boueres J,Ferrigno F, 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] Yelamos J, Farres J, Llacuna L, et al. PARP-1 and PARP-2: New players in tumourdevelopment[J]. Am J Cancer Res, 2011, 1(3): 328-346.[3] Wang L1,Mason KA,Ang KK,Buchholz T,Valdecanas D,Mathur A,Buser-Doepner C,Toniatti C,Milas L. 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.
Kinase assays
The reaction was conducted as for PARP-1 and PAPP-2 and included 0.3 nM of PARP-2, 4.4 x 105 DPM of [3H]-NAD and 7.5 uM NAD.
Cell lines
MDA-MB-436 and CAPAN-1 cell lines, human prostate epithelial (PREC) cells, Human mammary epithelial (HMEC) cells
Preparation method
Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reacting condition
0-20000 nM
Applications
In MDA-MB-436 cells carrying BRCA-1 mutations, MK-4827 displayed CC50 = 18 nM, while in CAPAN-1 cells with BRCA-2 mutant, MK-4827 displayed CC50 = 90 nM. In contrast, normal human prostate and mammary epithelial cells were 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.
Animal models
Female nude mice (Ncr Nu/Nu) xenograft model
Dosage form
25 mg/kg given twice daily or 50 mg/kg MK-4827 given once daily, oral
Application
The in vivo efficacy of MK-4827 was demonstrated in a BRCA-1 mutant MDA-MB-436 xenograft mode. When tumors reached an average volume of 150 mm3, mice were treated with MK-4827, dosing orally at either 100 mg/kg q.d. or 50 mg/kg b.i.d. Tumor regression was observed with both dosing regimes, and both were well tolerated, with no mortality. Less than 10% body weight loss was seen during the experiment.
Other notes
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References:
[1] Jones P, Altamura S, Boueres J, Ferrigno F, 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] Wang L, Mason KA, Ang KK,Buchholz T,Valdecanas D, Mathur A, Buser-Doepner C, Toniatti C, Milas L. 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.
