| Identification | Back Directory | [Name]
EPZ015666 | [CAS]
1616391-65-1 | [Synonyms]
EPZ015666
GSK3235025
GSK-3235025
N-[(2S)-3-(3,4-Dihydro-2(1H)-isoquinolinyl)-2-hydroxypropyl]-6-(3-oxetanylamino)-4-pyrimidinecarboxamide
(S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide
N-[(2S)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide | [Molecular Formula]
C20H25N5O3 | [MDL Number]
MFCD28411588 | [MOL File]
1616391-65-1.mol | [Molecular Weight]
383.44 |
| Chemical Properties | Back Directory | [Melting point ]
124-131°C | [Boiling point ]
686.4±55.0 °C(Predicted) | [density ]
1.331±0.06 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
Soluble in DMSO (up to 20 mg/ml) | [form ]
powder | [pka]
12.40±0.46(Predicted) | [color ]
white to beige | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. | [CAS DataBase Reference]
1616391-65-1 |
| Hazard Information | Back Directory | [Uses]
Protein arginine methyltransferases (PRMTs) target nuclear and cytoplasmic substrates and can alter protein actions and gene expression. PRMT5, which can methylate histones H2A, H3, and H4, ribonucleoproteins, and other proteins, is upregulated in several human cancers, including lymphomas. Moreover, suppression of PRMT5 expression induces lymphoma cell death. EPZ015666 is a potent, orally bioavailable inhibitor of PRMT5 (Ki = 5 nM). It displays more than 20,000-fold selectivity for PRMT5 over other PMTs. EPZ015666 acts by blocking the association of PRMT5 with methylosome protein 50, which is necessary for the formation of an active methyltransferase complex. EPZ015666 (100 mg/kg twice daily) blocks the growth of mantle cell lymphoma Z-138 xenografts, without significant body weight loss, in mice.[Cayman Chemical] | [Biochem/physiol Actions]
EPZ015666 (GSK3235025) is a protein arginine methyltransferase PRMT5 inhibitor with an IC50 value of of 22 nM in biochemical assays and no inhibition up to the maximum tested concentration of 50 μM against a panel of 20 other protein methyltransferases. Inhibition was uncompetitive with respect to SAM. EPZ015666 showed dose-dependent antitumor activity in multiple in vitro and in vivo mantle cell lymphoma (MCL) models with treatment of MCL cell lines leading to inhibition of SmD3 methylation and cell death. | [in vivo]
EPZ015666 (GSK3235025) is orally bioavailable and amenable to in vivo studies. We performed 21-d efficacy studies in severe combined immunodeficiency (SCID) mice bearing subcutaneous Z-138 and Maver-1 xenografts, with twice-daily (BID) oral dosing on four dose groups: 25, 50, 100 and 200 mg per kilogram of body weight (mg/kg). After 21 d of continuous dosing, animals are euthanized, and blood and tissues are analyzed to determine the relationship between methyl-mark pharmacodynamics and tumor-growth inhibition (TGI). EPZ015666 (GSK3235025) showed dose-dependent exposure and TGI after 21 d in both MCL models. Tumors in all EPZ015666 (GSK3235025) dose groups measured on day 21 showed statistically significant differences in weight, volume and tumor growth compared to vehicle-treated tumors. Dosing at 200 mg/kg BID induced tumor stasis in Z-138 cells, with >93% TGI after 21 d, whereas Maver-1 cells showed >70% TGI. Additionally, a third MCL xenograft is tested using the Granta-519 cell line, a fast-growing model that reached endpoint on day 18 and showed dose-dependent efficacy with 45% TGI in the 200 mg/kg group. EPZ015666 (GSK3235025) is well tolerated in all three models, with minimal bodyweight loss in the 200 mg/kg dose group and no other clinical observations[1]. | [IC 50]
PRMT5 | [storage]
Store at -20°C |
| Questions And Answer | Back Directory | [Description]
EPZ015666 (GSK3235025) is an orally available inhibitor of protein arginine methyltransferase-5 (PRMT5), which is involved in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL).EPZ015666 showed dose-dependent antitumor activity in multiplein vitroandin vivomantle cell lymphoma (MCL) models with treatment of MCL cell lines leading to inhibition of SmD3 methylation and cell death. Therefore, it is a potential drug candidate for future cancer therapy.
| [References]
Chan-Penebre, E, et al. "A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models." Nature Chemical Biology 11.6(2015):432.
Duncan, K. W., et al. "Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666." Acs Medicinal Chemistry Letters 7.2(2016):162-166.
http://www.sigmaaldrich.com/catalog/product/sigma/sml1421?lang=en®ion=US
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