EPZ015666 (GSK3235025)
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MedKoo CAT#: 407226

CAS#: 1616391-65-1

Description: EPZ015666, also known as GSK3235025, is a potent and selective and orally active PRMT5 inhibitor with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

Chemical Structure

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EPZ015666 (GSK3235025)
CAS# 1616391-65-1
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 407226
Name: EPZ015666 (GSK3235025)
CAS#: 1616391-65-1
Chemical Formula: C20H25N5O3
Exact Mass: 383.20
Molecular Weight: 383.452
Elemental Analysis: C, 62.65; H, 6.57; N, 18.26; O, 12.52

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 650 Ready to ship
200mg USD 1050 Ready to ship
500mg USD 2150 Ready to ship
1g USD 3250 Ready to ship
2g USD 5650 Ready to ship
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Synonym: EPZ015666; EPZ-015666; EPZ 015666; GSK3235025; GSK-3235025; GSK 3235025.

IUPAC/Chemical Name: (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide

InChi Key: ZKXZLIFRWWKZRY-KRWDZBQOSA-N

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

SMILES Code: O=C(C1=NC=NC(NC2COC2)=C1)NC[C@H](O)CN3CC4=C(C=CC=C4)CC3

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 with an IC50 of 22 nM.
In vitro activity: The impact of EPZ015666 on T-cell proliferation and viability was checked. EPZ015666 reduced T-cell proliferation with increasing concentrations. Cells were more sensitive to this inhibitor as suppression was already detectable at much lower doses, but even the highest tested concentration was less effective compared with MTA (Fig. 1E). Freshly isolated human CD8+ T cells were stimulated with autologous Mart-1 peptide-loaded mDCs in the presence or absence of 10 μmol/L EPZ015666. The frequency of Mart-1–specific CTLs was monitored by Mart-1 multimer staining over 18 days. No Mart-1+ cells could be detected in the presence of EPZ015666 after 18 days (Fig. 2D). In addition, there was a stronger reduction of Mart-1+ CTLs after 18 days compared with MTA-treated cells (Fig. 2B and E). Reference: Mol Cancer Ther. 2020 Feb;19(2):409-419. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=31712395
In vivo activity: EPZ015666 is orally bioavailable and amenable to in vivo studies. 21-d efficacy studies were performed 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−1). After 21 d of continuous dosing, animals were euthanized, and blood and tissues were analyzed to determine the relationship between methylmark pharmacodynamics and tumor-growth inhibition (TGI). EPZ015666 showed dose-dependent exposure and TGI after 21 d in both MCL models (Fig. 4c,d). Tumors in all EPZ015666 dose groups measured on day 21 showed statistically significant differences in weight, volume and tumor growth compared to vehicle-treated tumors. EPZ015666 was well tolerated in all three models, with minimal bodyweight loss in the 200 mg kg−1 dose group and no other clinical observations (Supplementary Fig. 16). To measure in vivo target inhibition, a highly quantitative SDMA ELISA was developed to allow for higher throughput and to complement the SDMA western blot. In the SDMA ELISA, Z-138 xenograft tumors collected on day 21 showed dose-dependent changes of >40% and >95% inhibition (>48% and >87% for Maver-1 tumors at day 21; >66% and >95% for Granta-519 tumors at day 18) of the methyl mark achieved at the lowest dose and highest dose, respectively (Fig. 4e,f and Supplementary Figs. 17–22). Reference: Nat Chem Biol. 2015 Jun;11(6):432-7. https://doi.org/10.1038/nchembio.1810

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 76.0 198.21
Ethanol 39.0 101.71

Preparing Stock Solutions

The following data is based on the product molecular weight 383.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, Duncan KW. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7. doi: 10.1038/nchembio.1810. Epub 2015 Apr 27. PMID: 25915199. 2. Strobl CD, Schaffer S, Haug T, Völkl S, Peter K, Singer K, Böttcher M, Mougiakakos D, Mackensen A, Aigner M. Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA. Mol Cancer Ther. 2020 Feb;19(2):409-419. doi: 10.1158/1535-7163.MCT-19-0189. Epub 2019 Nov 11. PMID: 31712395.
In vivo protocol: 1. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, Duncan KW. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7. doi: 10.1038/nchembio.1810. Epub 2015 Apr 27. PMID: 25915199.

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1: Rioux N, Duncan KW, Lantz RJ, Miao X, Chan-Penebre E, Moyer MP, Munchhof MJ,
Copeland RA, Chesworth R, Waters NJ. Species differences in metabolism of
EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5)
inhibitor. Xenobiotica. 2015 Aug 21:1-10. [Epub ahead of print] PubMed PMID:
26294260.


2: Rioux N, Duncan KW, Lantz RJ, Miao X, Chan-Penebre E, Moyer MP, Munchhof MJ,
Copeland RA, Chesworth R, Waters NJ. Species differences in metabolism of
EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5)
inhibitor. Xenobiotica. 2015 Jul 31:1-10. [Epub ahead of print] PubMed PMID:
26228443.


3: Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston
LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K,
Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O,
Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland
RA, Chesworth R, Duncan KW. A selective inhibitor of PRMT5 with in vivo and in
vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7. doi:
10.1038/nchembio.1810. Epub 2015 Apr 27. PubMed PMID: 25915199.