WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H407273
CAS#: 1616391-87-7
Description: GSK591, also known as EPZ015866 and GSK3203591, is a chemical probe for PRMT5. In an in vitro biochemical assay, GSK591 potently inhibits the PRMT5/MEP50 complex from methylating (histone) H4 with IC50 = 11 nM. In Z-138 cells, GSK591 inhibits the symmetric arginine methylation of SmD3 with EC50 = 56 nM. Further, GSK591 is selective for PRMT5 (up to 50 micromolar) relative to a panel of methyltransferases. (http://www.thesgc.org/chemical-probes/GSK59).
Hodoodo Cat#: H407273
Name: GSK591
CAS#: 1616391-87-7
Chemical Formula: C22H28N4O2
Exact Mass: 380.22
Molecular Weight: 380.492
Elemental Analysis: C, 69.45; H, 7.42; N, 14.73; O, 8.41
Synonym: GSK591; GSK-591; GSK 591; EPZ015866; EPZ-015866; EPZ 015866; GSK 3203591; GSK-3203591; GSK3203591.
IUPAC/Chemical Name: (S)-2-(cyclobutylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isonicotinamide
InChi Key: TWKYXZSXXXKKJU-FQEVSTJZSA-N
InChi Code: InChI=1S/C22H28N4O2/c27-20(15-26-11-9-16-4-1-2-5-18(16)14-26)13-24-22(28)17-8-10-23-21(12-17)25-19-6-3-7-19/h1-2,4-5,8,10,12,19-20,27H,3,6-7,9,11,13-15H2,(H,23,25)(H,24,28)/t20-/m0/s1
SMILES Code: O=C(NC[C@H](O)CN1CCC(C=CC=C2)=C2C1)C3=CC(NC4CCC4)=NC=C3
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: Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes . Overexpression of PRMTs has been implicated in various human diseases including cancer. To date, nine PRMTs have been identified and they are grouped into three categories: types I, II and III. Type II PRMTs, 5 and 9, catalyze symmetric dimethylation of arginine residues, however, PRMT5 is the predominant enzyme for this process. PRMT5 interacts with a number of binding partners that influence its substrate specificity. In particular, MEP50, a member of the WD40 family of proteins, is required for PRMT5 methyltransferase activity. (http://www.thesgc.org/chemical-probes/GSK59)
| Biological target: | GSK591 (EPZ015866) is a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) with an IC50 of 4 nM. |
| In vitro activity: | To further investigate the role of PRMT5 in lung cancer cell proliferation, PRTM5 specific inhibitor, GSK591, was used to black PRMT5 activity and cell proliferation was evaluated. It was found that proliferation of A549 and H1299 cells was markedly reduced in a dose dependent manner, whereas proliferation of IMR90 cells was almost no change (Figure 3A,B), indicating that this inhibitor has selectivity between cancer cells and normal cells. Next, the cell cycle proteins, cyclin E1 and cyclin D1, in A549 and H1299 cells were assessed upon the treatment of GSK591. It was found that cyclin E1 and cyclin D1 expression level was significantly decreased both in A549 and H1299 cells (Figure3C‐E). Taken together, these results suggest that blocking PRMT5 activity can prevent lung cancer cell proliferation and cell cycle progression. The effect of PRMT5 inhibitor GSK591 on the Akt activity was also examined. As shown in Figure5D‐F, Akt phosphorylation (Thr308 and Ser473) and GSK3β phosphorylation (Ser9) were significantly reduced when A549 and H1299 cells were treated with GSK591, whereas the PTEN and mTOR phosphorylation (Ser2442) did not change, indicating that PRMT5 regulation of Akt activity seems to be independent of PTEN and mTOR. In this study, it has been shown that cyclin E1 and cyclin D1 expression was significantly decreased in both A549 and H1299 cells when PRMT5 was down‐regulated or blocked by GSK591 (Figures2I and 3C). Reference: J Cell Mol Med. 2019 Feb; 23(2): 1333–1342. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349228/ |
| In vivo activity: | In order to further explore the enzymatic activity of PRMT5 was required or not for the lung cancer EMT, the xenograft mouse model was generated using normal A549 cells, and the null mice were treated with vehicle or PRMT5 specific inhibitor GSK591. Firstly, the expression level of SDMA, which is related to the enzymatic activity of PRMT5 was evaluated. As shown in Fig. 3B, the SDMA expression level was almost diminished in GSK591-treated tumors compared with vehicle treatment, indicating that the enzymatic activity of PRMT5 was blocked entirely. Next, the EMT-related gene expression using the same samples was expressed, and as shown in Fig. 3C, blocking of PRMT5 enzymatic activity markedly reduced the EMT genes, such as β-catenin, collagen I, vimentin, and ZEB1. To further confirm these findings, those proteins engaged in EMT were detected by Western blotting. As shown in Fig. 3D, E, EMT-related proteins, β-catenin, collagen I, and ZEB1, were distinctly decreased as well, indicating that enzymatic activity of PRMT5 is required to regulate EMT markers in human lung cancer. Collectively, the findings indicate that the enzyme activity of PRMT5 is closely related to EMT in human lung cancer. Reference: Cell Transplant. 2021 Jan-Dec; 30: 09636897211001772. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040599/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 76.0 | 199.74 | |
| Ethanol | 44.0 | 115.64 |
The following data is based on the product molecular weight 380.49 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.
| 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. Li Y, Yang Y, Liu X, Long Y, Zheng Y. PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol. Cell Transplant. 2019 Dec;28(12):1664-1673. doi: 10.1177/0963689719885083. Epub 2019 Oct 30. PMID: 31665911; PMCID: PMC6923546. 2. Zhang S, Ma Y, Hu X, Zheng Y, Chen X. Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. J Cell Mol Med. 2019 Feb;23(2):1333-1342. doi: 10.1111/jcmm.14036. Epub 2018 Nov 20. PMID: 30461193; PMCID: PMC6349228. 3. Yang L, Ma DW, Cao YP, Li DZ, Zhou X, Feng JF, Bao J. PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression. Theranostics. 2021 Jan 27;11(8):3742-3759. doi: 10.7150/thno.53023. PMID: 33664859; PMCID: PMC7914347. 4. Huang J, Zheng Y, Zheng X, Qian B, Yin Q, Lu J, Lei H. PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer. Cell Transplant. 2021 Jan-Dec;30:9636897211001772. doi: 10.1177/09636897211001772. PMID: 33829865; PMCID: PMC8040599. |
| In vitro protocol: | 1. Li Y, Yang Y, Liu X, Long Y, Zheng Y. PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol. Cell Transplant. 2019 Dec;28(12):1664-1673. doi: 10.1177/0963689719885083. Epub 2019 Oct 30. PMID: 31665911; PMCID: PMC6923546. 2. Zhang S, Ma Y, Hu X, Zheng Y, Chen X. Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. J Cell Mol Med. 2019 Feb;23(2):1333-1342. doi: 10.1111/jcmm.14036. Epub 2018 Nov 20. PMID: 30461193; PMCID: PMC6349228. |
| In vivo protocol: | 1. Yang L, Ma DW, Cao YP, Li DZ, Zhou X, Feng JF, Bao J. PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression. Theranostics. 2021 Jan 27;11(8):3742-3759. doi: 10.7150/thno.53023. PMID: 33664859; PMCID: PMC7914347. 2. Huang J, Zheng Y, Zheng X, Qian B, Yin Q, Lu J, Lei H. PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer. Cell Transplant. 2021 Jan-Dec;30:9636897211001772. doi: 10.1177/09636897211001772. PMID: 33829865; PMCID: PMC8040599. |
