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| Targets |
DS-437 is a dual inhibitor of protein arginine methyltransferase 5 (PRMT5) and PRMT7. PRMT5 is the primary type II arginine methyltransferase, responsible for catalyzing the formation of symmetric dimethylarginine (SDMA) on histone and non-histone proteins. It plays a critical role in various cellular processes, including transcription (as a repressor), splicing, cell cycle regulation, and DNA repair. PRMT7 is a type III arginine methyltransferase that catalyzes the formation of monomethylarginine (MMA). By inhibiting both enzymes, DS-437 blocks the arginine methylation events they catalyze, allowing researchers to study the functional consequences of this inhibition in cells. Its selectivity for PRMT5/7 over other methyltransferases is a key feature.
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| ln Vitro |
At equilibrium conditions (cofactor and substrate concentrations fixed at respective Km values), DS-437 can block the PRMT5-MEP50 complex's ability to methylate H4[1-24] peptide in a dose-dependent manner [1]. Its IC50 value is 5.9 ± 1.4 μM. The levels of CD8+ PD-1+ and total CD8+ T cells are raised by DS-437 [2].
DS-437 is a potent and selective dual inhibitor of PRMT5 and PRMT7. It inhibits PRMT5 with an IC₅₀ of 5.9 μM and PRMT7 with an IC₅₀ of 6 μM. Its selectivity is a standout feature; it shows a strong preference for PRMT5 and PRMT7 over 29 other human methyltransferases when tested at 50 μM. However, it is important to note that it also inhibits DNA methyltransferases DNMT3A and DNMT3B, with IC₅₀ values of 52 and 62 μM, respectively. This additional activity may be relevant at higher concentrations. The compound's mechanism of action is competitive with SAM, as it is a SAM analog. |
| ln Vivo |
There are some advantageous benefits of DS-437 (10 mg/kg; i.p.; 5 times weekly) on tumor growth inhibition. A more notable result was seen when DS-437 and anti-p185erbB2/neu antibody 4D5 were combined [1].
While specific in vivo activity data for DS-437 is not detailed in the provided search results, its potent and selective inhibition of PRMT5/7 suggests it would be a valuable tool for in vivo studies. As a SAM-competitive inhibitor, its activity in vivo would depend on its pharmacokinetic properties, including its ability to reach its targets and compete with endogenous SAM. By inhibiting PRMT5 and PRMT7, DS-437 would be expected to reduce the levels of SDMA and MMA on proteins in vivo, which could have downstream effects on gene expression, cell proliferation, and other biological processes. It could be used in mouse models to study the role of these enzymes in cancer and other diseases. |
| Enzyme Assay |
The in vitro enzyme assay for DS-437 typically measures its ability to inhibit the methyltransferase activity of PRMT5 and PRMT7. In these assays, purified recombinant PRMT5 or PRMT7 enzymes are incubated with a peptide substrate containing arginine residues and a radioactive or isotopically labeled methyl donor (such as ³H-SAM or ¹⁴C-SAM). The reaction proceeds, and the transfer of methyl groups to the substrate is measured. The assay is performed in the presence of varying concentrations of DS-437. The extent of methylation (e.g., by measuring the incorporation of radioactivity into the substrate) is quantified. A control without the inhibitor defines 100% enzyme activity. By plotting the percent inhibition versus the compound concentration, an IC₅₀ value can be determined.
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| Cell Assay |
In vitro cell-based assays for DS-437 evaluate its effects on arginine methylation and downstream cellular phenotypes. Cells are treated with DS-437 for a defined period, and the levels of SDMA and MMA on proteins are assessed by Western blot using specific antibodies. This confirms target engagement in a cellular context. Additionally, the compound's effects on cell proliferation, viability, and gene expression can be studied. For example, as PRMT5 is an oncogenic driver in some cancers, DS-437 could be used to study its role in cancer cell growth. These assays are crucial for understanding the functional consequences of PRMT5/7 inhibition.
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| Animal Protocol |
Animal/Disease Models: Six to Ten weeks old female balb/c (Bagg ALBino) mouse (bearing CT26Her2 tumor cells)[1]
Doses: 10 mg/kg Route of Administration: ip; 5 times a week Experimental Results: Had some beneficial effects on inhibiting tumor growth. Specific in vivo animal study protocols for DS-437 are not described in the provided literature. However, based on its mechanism as a PRMT5/7 inhibitor, typical studies would involve administering the compound to mouse models of cancer (e.g., xenograft models) to evaluate its antitumor activity. In such studies, tumor growth, survival, and markers of PRMT5/7 activity in the tumors would be assessed. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for DS-437 is not available in the provided search results. Its molecular weight is 397.45. As a research compound, its ADME properties would be characterized in preclinical studies.
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| Toxicity/Toxicokinetics |
Specific toxicity data for DS-437 is not publicly available. As a SAM-competitive inhibitor, its selectivity is good but not absolute, as it also inhibits DNMT3A/B at higher concentrations. This could be a source of off-target toxicity. It is classified as a research tool and is not intended for human use.
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| References | |
| Additional Infomation |
See also: DS-437 (notes moved to).
DS-437 is a valuable and selective research tool for studying the roles of PRMT5 and PRMT7 in arginine methylation. It is a SAM-competitive inhibitor that is widely used in epigenetic research. The compound has not received FDA approval for any indication. |
| Molecular Formula |
C15H23N7O4S
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|---|---|
| Molecular Weight |
397.45
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| Exact Mass |
397.153
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| CAS # |
1674364-87-4
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| PubChem CID |
122178085
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| Appearance |
Light brown to brown solid powder
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| Density |
1.7±0.1 g/cm3
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| Index of Refraction |
1.776
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| LogP |
0.16
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
27
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| Complexity |
505
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CCNC(=O)NCCSC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=CN=C32)N)O)O
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| InChi Key |
CACMCLIHCDTJHL-IDTAVKCVSA-N
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| InChi Code |
InChI=1S/C15H23N7O4S/c1-2-17-15(25)18-3-4-27-5-8-10(23)11(24)14(26-8)22-7-21-9-12(16)19-6-20-13(9)22/h6-8,10-11,14,23-24H,2-5H2,1H3,(H2,16,19,20)(H2,17,18,25)/t8-,10-,11-,14-/m1/s1
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| Chemical Name |
1-[2-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]ethyl]-3-ethylurea
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| Synonyms |
DS437 DS 437 DS-437
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~314.50 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5160 mL | 12.5802 mL | 25.1604 mL | |
| 5 mM | 0.5032 mL | 2.5160 mL | 5.0321 mL | |
| 10 mM | 0.2516 mL | 1.2580 mL | 2.5160 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.
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