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MedKoo Cat#: 206819 | Name: GSK-3326595
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pemrametostat, also known as GSK-3326595 and EPZ015938, is an orally active, potent and selective inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models.GSK-3326595 halts proliferation and induces apoptosis in numerous solid and hematologic tumor cell lines. It has been shown to have potent anti-tumor activity in vivo in animal models.

Chemical Structure

GSK-3326595
GSK-3326595
CAS#1616392-22-3 (free base)

Theoretical Analysis

MedKoo Cat#: 206819

Name: GSK-3326595

CAS#: 1616392-22-3 (free base)

Chemical Formula: C24H32N6O3

Exact Mass: 452.2536

Molecular Weight: 452.56

Elemental Analysis: C, 63.70; H, 7.13; N, 18.57; O, 10.61

Price and Availability

Size Price Availability Quantity
10mg USD 110.00 Ready to ship
25mg USD 245.00 Ready to ship
50mg USD 425.00 Ready to ship
100mg USD 725.00 Ready to ship
200mg USD 1,250.00 Ready to ship
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Related CAS #
1848944-46-6 (succinate) 1616392-22-3 (free base)
Synonym
GSK-3326595; GSK 3326595; GSK3326595; EPZ015938; EPZ 015938; EPZ-015938; Pemrametostat
IUPAC/Chemical Name
(S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide
InChi Key
JLCCNYVTIWRPIZ-NRFANRHFSA-N
InChi Code
InChI=1S/C24H32N6O3/c1-17(31)30-10-7-20(8-11-30)28-23-12-22(26-16-27-23)24(33)25-13-21(32)15-29-9-6-18-4-2-3-5-19(18)14-29/h2-5,12,16,20-21,32H,6-11,13-15H2,1H3,(H,25,33)(H,26,27,28)/t21-/m0/s1
SMILES Code
O=C(C)N1CCC(NC2=NC=NC(C(NC[C@H](O)CN3CCC(C=CC=C4)=C4C3)=O)=C2)CC1
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
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:
GSK-3326595 is an inhibitor of protein arginine methyltransferase 5 (PRMT5) with an IC50 of 6.2 nM.
In vitro activity:
To investigate the mechanism of the growth attenuation by PRMT5 inhibitors, the effects of GSK3326595 on the distribution of Z-138 cells in the phases of cell cycle were evaluated (Fig. 2C). Propidium iodide stained nuclei of Z-138 cells treated with a range of concentrations of GSK3326595 for 1, 2, 3, 5, 7, or 10 days (Fig. 2D) were evaluated by flow cytometry. A dose- and time-dependent G1 arrest (an increase in 2 N DNA) was evident in Z-138 cells treated for 2, 3, and 5 days with a reciprocal decrease in >2 N & <4 N, and 4 N cell populations. After 5 days of treatment, an increase in the sub-2N population (cell death) was observed. The cell cycle profiles of lymphoma and breast cancer cell lines of varying sensitivities to GSK3326595 were also evaluated (Fig. 2E, 3 days post treatment). GSK3326595 treatment led to an increase in the 2 N population in the most sensitive MCL cell lines, Z-138 and JVM-2 (gIC50  < 100 nM) while having no effect on cell cycle distribution in the less sensitive MCL cell lines, JEKO-1, MINO, and REC-1 (gIC50 > 100 nM). When tested in breast cancer cell lines, GSK3326595 treatment resulted in an accumulation of MCF-7 cells in the 2 N population after 2 and 7 days of treatment, while in MDA-MB-468 cells the treatment resulted in a decrease in 2 N, and an increase in sub-2N, 4 N and >4 N with 7 and 10 days of treatment. In both MDA-MB-468 and MCF-7, an accumulation of the sub-2N population was observed after 7 and 10 days of treatment, respectively (Fig. 2F). The effects of GSK3326595 in lymphoma and breast cancer cell lines suggest that PRMT5 inhibition results in context-dependent effects on cell cycle (a 2 N population increase was observed only in a subset of sensitive models, while a decrease in 2 N and an increase in 4 N was observed in MDA-MB-468). Reference: Sci Rep. 2018 Jun 26;8(1):9711. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018746/
In vivo activity:
Protein arginine methyltransferase 5 (PRMT5) controls diverse cellular processes and is implicated in cancer development and progression. An inverse correlation exists between PRMT5 function and antitumor immunity. PRMT5 inhibition antagonized melanoma growth in immunocompetent but not immunocompromised mice and upregulated an antitumor immune gene signature. PRMT5 methylation of IFI16 (interferon gamma inducible protein 16) and its murine homologue IFI204, which are cGAS (cyclic GMP-AMP synthase)/STING (stimulator of interferon genes) pathway components, attenuated cytosolic-DNA-induced interferon and chemokine production. PRMT5 also inhibited transcription of NLRC5 (NLR Family CARD Domain Containing 5), which regulates genes implicated in MHCI antigen presentation. Correspondingly, PRMT5 knockdown augmented interferon and chemokine production and increased MHCI expression. Elevated expression of IFI16/IFI204 and NLRC5 was associated with decreased melanoma growth in murine models and prolonged survival of melanoma patients. Notably, combination of pharmacological (GSK3326595) or genetic (shRNA) inhibition of PRMT5 with immune checkpoint therapy limited growth of murine melanoma tumors (B16F10 and YUMM1.7) and enhanced therapeutic efficacy. Reference: Sci Transl Med. 2020 Jul 8;12(551):eaaz5683. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508354/
Solvent mg/mL mM
Solubility
DMSO 60.5 133.68
Ethanol 32.0 70.71
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 452.56 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:
1. AbuHammad S, Cullinane C, Martin C, Bacolas Z, Ward T, Chen H, Slater A, Ardley K, Kirby L, Chan KT, Brajanovski N, Smith LK, Rao AD, Lelliott EJ, Kleinschmidt M, Vergara IA, Papenfuss AT, Lau P, Ghosh P, Haupt S, Haupt Y, Sanij E, Poortinga G, Pearson RB, Falk H, Curtis DJ, Stupple P, Devlin M, Street I, Davies MA, McArthur GA, Sheppard KE. Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000. doi: 10.1073/pnas.1901323116. Epub 2019 Aug 22. Erratum in: Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9644-9645. PMID: 31439820; PMCID: PMC6731642. 2. Kim H, Kim H, Feng Y, Li Y, Tamiya H, Tocci S, Ronai ZA. PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Sci Transl Med. 2020 Jul 8;12(551):eaaz5683. doi: 10.1126/scitranslmed.aaz5683. PMID: 32641491; PMCID: PMC7508354.
In vitro protocol:
1. AbuHammad S, Cullinane C, Martin C, Bacolas Z, Ward T, Chen H, Slater A, Ardley K, Kirby L, Chan KT, Brajanovski N, Smith LK, Rao AD, Lelliott EJ, Kleinschmidt M, Vergara IA, Papenfuss AT, Lau P, Ghosh P, Haupt S, Haupt Y, Sanij E, Poortinga G, Pearson RB, Falk H, Curtis DJ, Stupple P, Devlin M, Street I, Davies MA, McArthur GA, Sheppard KE. Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000. doi: 10.1073/pnas.1901323116. Epub 2019 Aug 22. Erratum in: Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9644-9645. PMID: 31439820; PMCID: PMC6731642.
In vivo protocol:
1. Kim H, Kim H, Feng Y, Li Y, Tamiya H, Tocci S, Ronai ZA. PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Sci Transl Med. 2020 Jul 8;12(551):eaaz5683. doi: 10.1126/scitranslmed.aaz5683. PMID: 32641491; PMCID: PMC7508354.
1. Tao H, Yan X, Zhu K, Zhang H. Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations. Chem Pharm Bull (Tokyo). 2019;67(4):382-388. doi: 10.1248/cpb.c18-00980. PMID: 30930442. 2. Shao J, Zhu K, Du D, Zhang Y, Tao H, Chen Z, Jiang H, Chen K, Luo C, Duan W. Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation. Eur J Med Chem. 2019 Feb 15;164:317-333. doi: 10.1016/j.ejmech.2018.12.065. Epub 2018 Dec 26. PMID: 30605830. 3. Zhu K, Shao J, Tao H, Yan X, Luo C, Zhang H, Duan W. Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity. J Comput Aided Mol Des. 2019 Aug;33(8):775-785. doi: 10.1007/s10822-019-00214-y. Epub 2019 Jul 16. PMID: 31312965.