Background
EPZ015666 is a potent and selective inhibitor of PRMT5 with IC50 value of 22 nM [1].
Protein arginine methyltransferase-5 (PRMT5) is an enzyme that plays an important role in many cellular processes including tumorigenesis [1].
EPZ015666 is an orally bioavailable PRMT5 inhibitor. In a competitive inhibition model, EPZ015666 inhibited PRMT5 with Ki value of 5 nM and exhibited >20000-fold selectivity over 20 other protein methyltransferases (PMTs). In MCL cell lines Z-138, Mino, Maver-1, Granta-519 and Jeko-1, EPZ015666 decreased the level of SmD3, which was a PRMT5 substrate in a concentration-dependent way. Also, EPZ015666 reduced SmD3me2s in all cell lines. The cellular thermal shift assay (CETSA) in A375 cells showed that EPZ015666 specifically bound to PRMT5. EPZ015666 showed potent antiproliferative effects with IC50 values of 96, 450 and 61-904 nM for Z-138, Maver-1 and additional MCL cell lines respectively in a concentration-dependent way [1].
In SCID mice bearing Z-138 and Maver-1 xenografts, EPZ015666 (25, 50, 100 and 200 mg/kg) showed tumor-growth inhibition (TGI) in a dose-dependent way [1].
Reference:
[1].? Chan-Penebre E, Kuplast KG, Majer CR, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol, 2015, 11(6): 432-437.
Protocol
| Cell experiment [1]: |
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Cell lines
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Z-138 and Maver-1 cells
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Preparation method
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The solubility of this compound in DMSO is > 19.2 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
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Reacting condition
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0.0007 ~ 5 μM
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Applications
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In Z-138 and Maver-1 cells, EPZ015666 potently inhibited cell proliferation in a concentration-dependent manner, with the IC50 values of 96 nM and 450 nM, respectively.
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| Animal experiment [1]: |
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Animal models
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SCID mice bearing Z-138 and Maver-1 xenografts
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Dosage form
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25, 50, 100 and 200 mg/kg; p.o.; b.i.d., for 21 days
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Applications
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EPZ015666, at all indicated doses, significantly affected weight, volume and tumor growth of SCID mice bearing Z-138 and Maver-1 xenografts. At the dose of 200 mg/kg, EPZ015666 induced tumor stasis in Z-138 cells and Maver-1 cells, with the TGI values of > 93% and > 70%, respectively.
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Other notes
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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.
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参考文献:
[1]. Chan-Penebre E, Kuplast KG, Majer CR, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol, 2015, 11(6): 432-437.
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