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Valemetostat tosylate (DS3201; DS3201b; Ezharmia), the tosylate salt of Valemetostat, is an investigational and orally bioavailable dual EZH1/2 inhibitor with potential anticancer activity. As of September 2022, Valemetostat has been approved for treatment of aggressive ATL in Japan.
| Targets |
With IC50 values less than 10 nM, valemetostat tosylate (1-1000 nM) substantially and selectively inhibits EZH1 and EZH2 [3]. H3K27me3 is efficiently increased and unintentional increases are prevented by valemetostat tosylate (100 nM; 7 d) [3]. 0.1-100 nM; 7 d) Uses low-dose therapy to effectively block the H3K27me3 pore size model in sensitive cells [3].
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| ln Vitro |
With IC50 values less than 10 nM, valemetostat tosylate (1-1000 nM) substantially and selectively inhibits EZH1 and EZH2 [3]. H3K27me3 is efficiently increased and unintentional increases are prevented by valemetostat tosylate (100 nM; 7 d) [3]. 0.1-100 nM; 7 d) Uses low-dose therapy to effectively block the H3K27me3 pore size model in sensitive cells [3].
Valemetostat (also called (R)-OR-S2 or DS-3201) is a potent SAM-competitive dual inhibitor of EZH1 and EZH2 methyltransferase activities with IC₅₀ values ≤ 10 nM against both enzymes. In cell-based assays using HCT116 cells, it reduces global H3K27me3 levels. It demonstrates superior anti-proliferative activity compared to EZH2-selective inhibitors (GSK126, E7438) across a panel of 23 hematological malignancy cell lines, including adult T-cell leukemia-lymphoma (ATL), peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL) with both wild-type and mutant EZH2, Burkitt lymphoma (BL), primary effusion lymphoma (PEL), and MLL-rearranged leukemia. Growth inhibition IC₅₀ values were all below 1000 nM, with ATL and other T-cell lymphomas being particularly sensitive. In ATL cell lines (TL-Om1) and primary ATL cells, treatment with 100 nM valemetostat for 7 days effectively removed H3K27me3 marks, evicted both EZH1 and EZH2 from chromatin, reactivated expression of silenced genes (e.g., SLA, PAG1, BTG1, BTG2), deactivated NF-κB signaling, and induced apoptosis. The dual inhibition was more effective than a 10-fold higher dose of the EZH2-selective inhibitor GSK126 in removing H3K27me3 and inhibiting cell growth. Synthetic lethality was also observed in cancer cell models with inactivation of chromatin-associated genes (ARID1A, KDM6A, BAP1, SMARCB1) or infection with oncoviruses (HTLV-1, EBV). Treatment did not disrupt the core PRC2 complex composition but reduced chromatin occupancy of EZH1/EZH2. [3] |
| ln Vivo |
In immunodeficient (NOD/SCID) mice subcutaneously inoculated with ATL-derived TL-Om1 cells, oral administration of valemetostat (as OR-S1, a related EZH1/2 dual inhibitor from the same series) at 200 mg/kg daily completely prevented tumor engraftment. In a therapeutic setting, oral administration of OR-S1 (100-200 mg/kg daily) starting from day 14 post-inoculation significantly inhibited the growth of established TL-Om1 xenograft tumors and inhibited liver metastasis, without causing significant body weight loss. [3]
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| Enzyme Assay |
Methyltransferase activity assays for PRC2-EZH2 and PRC2-EZH1 were performed in vitro using a scintillation proximity assay. The reaction mixture contained Tris-HCl buffer (pH 8.8), MgCl₂, DTT, BSA, unlabeled S-adenosylmethionine (SAM), tritium-labeled SAM ([³H]-SAM), and a biotinylated histone H3 peptide as substrate. Recombinant PRC2-EZH2 or PRC2-EZH1 complex was added to initiate the reaction. The transfer of the tritiated methyl group from [³H]-SAM to the biotinylated H3 peptide was measured after incubation at room temperature for 2 hours in streptavidin-coated plates. For IC₅₀ determination, test compounds like valemetostat were serially diluted and added to the reaction mixture. Data were analyzed using a sigmoidal dose-response model. [3]
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| Cell Assay |
For anti-proliferation assays, lymphoma or solid tumor cell lines were seeded in multi-well plates and treated with a range of concentrations of valemetostat or other EZH inhibitors dissolved in DMSO. Cells were cultured for 14 days, with passaging every 3-4 days into fresh medium containing the compound. Cell viability/growth was assessed at the end of the treatment period. For primary ATL cell viability assays, patient-derived PBMCs were cultured with IL-2 and treated with inhibitors for 7 days, followed by cell counting assays. To assess H3K27me3 reduction in cells, HCT116 cells were treated with compounds for 3 days, and global H3K27me3 levels were quantified using a specific cellular detection kit based on AlphaLISA technology. For chromatin immunoprecipitation (ChIP) assays, cells were cross-linked with formaldehyde, lysed, and chromatin was sheared by micrococcal nuclease digestion and sonication. Sheared chromatin was immunoprecipitated with antibodies against H3K27me3, EZH1, EZH2, or other histone marks. Precipitated DNA was purified and analyzed by quantitative PCR or microarray (ChIP-chip) to determine enrichment at specific genomic loci. [3]
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6J mice performed chronic and acute running exercise 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 levels increased Dramatically after exercise, EZH1 levels diminished slightly, EZH2 levels increased, and phosphorylated AMPK levels increased. Inhibits myonuclear H3K27me3 accumulation during training and leads to failure of adaptive changes. For tumor prevention studies, NOD/SCID mice were subcutaneously inoculated with TL-Om1 cells in the post-auricular region. Starting from the day of inoculation, mice were orally administered valemetostat (as OR-S1) suspended in a 0.5% (w/v) methylcellulose solution at a dose of 200 mg/kg daily. Tumor formation was monitored. For therapeutic efficacy studies, NOG mice were subcutaneously inoculated with TL-Om1 cells. After tumors were established (day 14), mice were randomized into groups and treated orally with OR-S1 at doses of 100 or 200 mg/kg daily. Tumor dimensions were measured regularly to calculate volume, and body weight was monitored. [3] |
| Toxicity/Toxicokinetics |
Repeated administration of valemetostat (as part of the OR-S family of drugs) in preclinical models did not cause any serious in vitro or in vivo toxicity. In mouse xenograft studies, daily oral administration of 100–200 mg/kg of OR-S1 did not result in significant weight loss in the mice. [3]
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| References |
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| Additional Infomation |
Valemetostat tosylate is the tosylate form of Valemetostat, an orally administered selective inhibitor of histone lysine methyltransferases EZH1 and EZH2 with potential antitumor activity. Oral 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 cancer cells expressing EZH1/2. EZH1/2 are histone lysine methyltransferase (HMT) enzymes and the catalytic subunit of 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. Valmetostat is a dual inhibitor of EZH1 and EZH2. This study provides a mechanistic explanation for the dual-targeting strategy, showing that EZH1 and EZH2 are co-expressed in many lymphomas and have antagonistic/interfering functions in chromatin. Inhibition of EZH2 alone leads to compensatory recruitment of EZH1 and residual H3K27me3, while dual inhibition effectively remodels the oncogenic epigenome. The drug has shown potent activity against a variety of hematologic malignancies, especially against tumors that overexpress EZH2 (e.g., adult T-cell leukemia/lymphoma (ATL), peripheral T-cell lymphoma (PTCL)) or carry mutations in epigenetic modification genes (ARID1A, SMARCA4, SMARCB1, KDM6A, BAP1, KMT2D). It is also effective against precancerous cells with epigenetic disturbances caused by oncogenic viruses (HTLV-1, EBV). Based on these results, a phase I clinical trial for T-cell and B-cell non-Hodgkin lymphomas, including ATL, has been initiated. [3]
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| Molecular Formula |
C33H42CLN3O7S
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|---|---|
| Molecular Weight |
660.220487117767
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| Exact Mass |
659.243
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| CAS # |
1809336-93-3
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| Related CAS # |
Valemetostat;1809336-39-7
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| PubChem CID |
126482037
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
45
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| Complexity |
1090
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1=CC(C(NCC2C(NC(C)=CC=2C)=O)=O)=C(C)C2=C1O[C@](C)(C1CCC(CC1)N(C)C)O2.S(C1C=CC(C)=CC=1)(=O)(=O)O
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| InChi Key |
JSBKGJUYSLVFPF-RRKMXGHKSA-N
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| InChi Code |
InChI=1S/C26H34ClN3O4.C7H8O3S/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;1-6-2-4-7(5-3-6)11(8,9)10/h11-12,17-18H,7-10,13H2,1-6H3,(H,28,31)(H,29,32);2-5H,1H3,(H,8,9,10)/t17?,18?,26-;/m1./s1
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| Chemical Name |
(2R)-7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;4-methylbenzenesulfonic acid
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| Synonyms |
DS-3201 tosylateDS3201 tosylate Ezharmia
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~100 mg/mL (~151.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.15 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 (3.15 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 (3.15 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 | 1.5146 mL | 7.5732 mL | 15.1465 mL | |
| 5 mM | 0.3029 mL | 1.5146 mL | 3.0293 mL | |
| 10 mM | 0.1515 mL | 0.7573 mL | 1.5146 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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