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Purity: ≥98%
Description: EPZ015666 (GSK-3235025), an analog of EPZ-015866, is a potent, selective and orally bioavailable inhibitor of PRMT5 (protein arginine methyltransferase) with antineoplastic activity. It inhibits the enzymatic activity of PRMT5 with Ki of 5-22 nM in biochemical assays, and displays >20,000-fold selectivity for PRMT5 over other PMTs.
| ln Vitro |
EPZ015666 (GSK3235025) suppresses SmD3 methylation and cell death in MCL cell lines, showing IC50 values in the nanomolar range [1]. EPZ015666 (GSK3235025) is a strong peptide-competitive and SAM-cooperative inhibitor with over 10,000-fold selectivity against PRMT5 compared to other methyltransferases[2].
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| ln Vivo |
EPZ015666 (GSK3235025) is bioavailable when taken orally and suitable for in vivo research. We conducted 21-day efficacy studies in mice with severe combined immunodeficiency (SCID) that were given subcutaneous Z-138 and Maver-1 xenografts. The mice were given oral doses twice a day (BID) at four different dose levels: 25, 50, 100, and 200 mg/kg. The animals are put to sleep after receiving a dose continuously for 21 days, and samples of blood and tissues are examined to ascertain the connection between tumor-growth inhibition (TGI) and methyl-mark pharmacodynamics. In both MCL models, EPZ015666 (GSK3235025) demonstrated dose-dependent exposure and TGI after 21 days. When weighed against vehicle-treated tumors, all EPZ015666 (GSK3235025) dose groups' tumors demonstrated statistically significant differences in weight, volume, and tumor growth on day 21. 200 mg/kg BID dosage resulted in tumor stasis in Z-138 cells, which showed >93% TGI after 21 days, while Maver-1 cells only displayed >70% TGI. Furthermore, the Granta-519 cell line, a rapidly expanding model that reached endpoint on day 18 and demonstrated dose-dependent efficacy with 45% TGI in the 200 mg/kg group, is used to test a third MCL xenograft. With little bodyweight loss in the 200 mg/kg dose group and no additional clinical observations, EPZ015666 (GSK3235025) is well tolerated in all three models[1].
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| References |
[1]. Chan-Penebre E, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7.
[2]. Kryukov GV, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016 Mar 11;351(6278):1214-8 |
| Molecular Formula |
C20H25N5O3
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| Molecular Weight |
383.44
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| CAS # |
1616391-65-1
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| Related CAS # |
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| SMILES |
O=C(C1=NC=NC(NC2COC2)=C1)NC[C@H](O)CN3CC4=C(C=CC=C4)CC3
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| InChi Key |
ZKXZLIFRWWKZRY-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C20H25N5O3/c26-17(10-25-6-5-14-3-1-2-4-15(14)9-25)8-21-20(27)18-7-19(23-13-22-18)24-16-11-28-12-16/h1-4,7,13,16-17,26H,5-6,8-12H2,(H,21,27)(H,22,23,24)/t17-/m0/s1
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| Chemical Name |
(S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide
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| Synonyms |
GSK-3235025; GSK 3235025; GSK3235025; EPZ-015666; EPZ 015666; EPZ015666.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6080 mL | 13.0398 mL | 26.0797 mL | |
| 5 mM | 0.5216 mL | 2.6080 mL | 5.2159 mL | |
| 10 mM | 0.2608 mL | 1.3040 mL | 2.6080 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Co-crystal structures of PRMT5:MEP50 (green) with compound8(A, magenta), compound9(B, orange), compound10(C, yellow), and compound15(D, cyan).ACS Med Chem Lett.2015 Dec 2;7(2):162-6. |
Plot of cLogD vs scaled clearance (CL) from human microsomes (A) and mouse liver microsomes (B).Plot of proliferation IC50in Z-138 cells vs observed CL in mouse PK (C) and percentage oral bioavailability %F from mouse PK (D) dosed at 2 mg/kg IV and 10 mg/kg PO.ACS Med Chem Lett.2015 Dec 2;7(2):162-6. |
Plasma PK profile ofEPZ015666in male CD-1 mouse following single dose administration at 10 and 100 mg/kg p.o. Methyl mark IC90corrected for PPB shown as dotted line. ACS Med Chem Lett.2015 Dec 2;7(2):162-6. |
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