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| Targets |
Valemetostat targets enhancer of zeste homolog 1 (EZH1) and enhancer of zeste homolog 2 (EZH2), the catalytic subunits of polycomb repressive complex 2 (PRC2). PRC2 is an epigenetic regulatory complex that catalyzes the methylation of histone H3 lysine 27 (H3K27), a mark associated with transcriptional repression. EZH2 is frequently overexpressed or mutated in various cancers, leading to aberrant H3K27 methylation and silencing of tumor suppressor genes. EZH1 can compensate for EZH2 loss, making dual EZH1/2 inhibition more effective than EZH2-selective inhibition. Valemetostat inhibits PRC2 containing EZH1 or EZH2 with IC50 values of 8.4 nM and 2.5 nM, respectively.
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| ln Vitro |
With IC50 values <10 nM, valemetostat (1-1000 nM) substantially and selectively inhibits EZH1 and EZH2 [3]. H3K27me3 is efficiently eliminated by valemetostat (100 nM; 7 d) and unintentional increases in H3K27me3 are avoided [3]. Valemetostat (0.1-100 nM; 7 d) significantly suppresses H3K27me3 in lymphoma types that are sensitive to its effects in low doses [3].
In vitro, Valemetostat is a potent inhibitor of EZH1 and EZH2, with IC50 values of 8.4 nM and 2.5 nM, respectively. The compound inhibits PRC2 activity and reduces H3K27 methylation. Its potency and selectivity for EZH1 and EZH2 over other histone methyltransferases have been characterized in cell-free enzymatic assays. Valemetostat has demonstrated antiproliferative activity in cancer cell lines. |
| ln Vivo |
Following exercise training, valemetostat (0.01 mg/g; intraperitoneal injection; once) inhibits alterations in H3K27me3.
In vivo, Valemetostat has been evaluated for the treatment of relapsed/refractory adult T-cell leukemia/lymphoma (ATL) and other hematological malignancies. By inhibiting EZH1 and EZH2 and reducing H3K27 methylation, the compound reactivates silenced tumor suppressor genes and inhibits tumor growth. Clinical trials have been conducted to evaluate its safety and efficacy in patients with hematological malignancies. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for Valemetostat involve measuring its inhibitory activity against EZH1 and EZH2 using purified PRC2 complexes. PRC2 enzymatic activity is measured using histone H3 peptide substrates and S-adenosylmethionine (SAM) as the methyl donor. Methyltransferase activity is quantified by measuring the incorporation of methyl groups into the histone substrate, and IC50 values are calculated from inhibition curves.
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| Cell Assay |
In vitro cell-based experiments for Valemetostat are conducted using cancer cell lines, including lymphoma and leukemia cell lines. Cells are treated with Valemetostat at varying concentrations, and H3K27 methylation levels are measured by Western blot. Cell proliferation, apoptosis, and gene expression changes are assessed.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6J mice, chronic, acute running or no exercise [1]
Doses: 0.01 mg/g Route of Administration: intraperitoneal (ip) injection; 0.01 mg/g; 30 minutes before the start of running. Experimental Results: H3K27me3 after exercise The levels were Dramatically increased, EZH1 levels were slightly diminished, EZH2 levels were upregulated, and phosphorylated AMPK levels were increased. Inhibits myonuclear H3K27me3 accumulation during training and leads to failure of adaptive changes. In vivo animal experiments for Valemetostat are performed in xenograft mouse models of hematological malignancies. Valemetostat is administered orally, and tumor growth, H3K27 methylation, and survival are assessed. Clinical trials in humans have also been conducted. |
| ADME/Pharmacokinetics |
Valemetostat is a small molecule (MW 488.02, formula C26H34ClN3O4) with suitable physicochemical properties for oral administration. The compound has a molecular weight of 488.02 g/mol. Detailed pharmacokinetic parameters are available from clinical studies.
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| Toxicity/Toxicokinetics |
Preclinical and clinical toxicology studies have been conducted to evaluate the safety profile of Valemetostat. The compound is generally well-tolerated at therapeutic doses. Clinical trials have evaluated the safety and efficacy of Valemetostat in patients with relapsed/refractory adult T-cell leukemia/lymphoma and other hematological malignancies. The safety profile supports its continued development.
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| References |
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| Additional Infomation |
Valemetostat is an orally administered selective inhibitor of histone lysine methyltransferases EZH1 and EZH2 with potential antitumor activity. After oral administration, valemetostat selectively inhibits the wild-type and mutant activities of EZH1 and EZH2. Inhibition of EZH1/2 specifically prevents methylation of histone H3 at lysine 27 (H3K27). Decreased histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and leads to reduced proliferation of EZH1/2-expressing cancer cells. EZH1/2 are histone lysine methyltransferase (HMT) enzymes and the catalytic subunit of the polycomb repressor complex 2 (PRC2). They are overexpressed or mutated in various cancer cells and play a crucial role in tumor cell proliferation, progression, stem cell self-renewal, and migration.
Valemetostat is also known as DS-3201. It is a dual EZH1/2 inhibitor being developed for the treatment of hematological malignancies, including adult T-cell leukemia/lymphoma. Its dual inhibition of EZH1 and EZH2 provides a more comprehensive approach to targeting PRC2-mediated gene silencing than EZH2-selective inhibitors. The compound is an investigational agent and is not approved for clinical use. |
| Molecular Formula |
C26H34CLN3O4
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|---|---|
| Molecular Weight |
488.02
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| Exact Mass |
487.223
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| CAS # |
1809336-39-7
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| Related CAS # |
Valemetostat tosylate;1809336-93-3
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| PubChem CID |
126481870
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| Appearance |
White to off-white solid powder
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| Density |
1.26±0.1 g/cm3(Predicted)
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| Boiling Point |
610.0±55.0 °C(Predicted)
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
879
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC(=C(C(=O)N1)CNC(=O)C2=CC(=C3C(=C2C)O[C@@](O3)(C)C4CCC(CC4)N(C)C)Cl)C
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| InChi Key |
SSDRNUPMYCFXGM-UYPAYLBCSA-N
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| InChi Code |
InChI=1S/C26H34ClN3O4/c1-14-11-15(2)29-25(32)20(14)13-28-24(31)19-12-21(27)23-22(16(19)3)33-26(4,34-23)17-7-9-18(10-8-17)30(5)6/h11-12,17-18H,7-10,13H2,1-6H3,(H,28,31)(H,29,32)/t17-,18-,26-/m1/s1
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| Chemical Name |
(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
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| Synonyms |
DS3201Valemetostat DS-3201 DS 3201 DS-3201bEzharmia
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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 : ~70 mg/mL (~143.44 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.25 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 50.0 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: ≥ 5 mg/mL (10.25 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 50.0 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: ≥ 3.5 mg/mL (7.17 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 | 2.0491 mL | 10.2455 mL | 20.4910 mL | |
| 5 mM | 0.4098 mL | 2.0491 mL | 4.0982 mL | |
| 10 mM | 0.2049 mL | 1.0245 mL | 2.0491 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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