Valemetostat (formerly known as DS-3201; DS-3201b; Ezharmia) is a first-in-class, investigational and oral EZH1/2 dual inhibitor with anticancer activity. It targets epigenetic regulation by inhibiting the EZH1, as well as EZH2 enzymes, which regulate gene expression by acting through histone methylation. A new drug application seeking the approval of valemetostat tosylate (DS-3201b) for use in the treatment of patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATL) has been submitted to the Japanese Ministry of Health, Labour, and Welfare. As of September 2022, Valemetostat is the first dual EZH1/2 inhibitor approved for treatment of aggressive ATL in Japan. Valemetostat is being evaluated in Phase I clinical development for several types of NHLs, including ATL, peripheral T-cell lymphoma (PTCL) and B-cell lymphomas.
Physicochemical Properties
| Molecular Formula | C26H34CLN3O4 |
| Molecular Weight | 488.02 |
| Exact Mass | 487.223 |
| CAS # | 1809336-39-7 |
| Related CAS # | Valemetostat tosylate;1809336-93-3 |
| PubChem CID | 126481870 |
| Appearance | White to off-white solid powder |
| Density | 1.26±0.1 g/cm3(Predicted) |
| Boiling Point | 610.0±55.0 °C(Predicted) |
| LogP | 4.4 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 34 |
| Complexity | 879 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CC1=CC(=C(C(=O)N1)CNC(=O)C2=CC(=C3C(=C2C)O[C@@](O3)(C)C4CCC(CC4)N(C)C)Cl)C |
| InChi Key | SSDRNUPMYCFXGM-UYPAYLBCSA-N |
| 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 |
| 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 |
| Synonyms | DS3201Valemetostat DS-3201 DS 3201 DS-3201bEzharmia |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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]. |
| ln Vivo | Following exercise training, valemetostat (0.01 mg/g; intraperitoneal injection; once) inhibits alterations in H3K27me3. |
| 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. |
| References |
[1]. Daiichi Sankyo’s EZH1/2 Dual Inhibitor Valemetostat (DS-3201) Receives SAKIGAKE Designation for Treatment of Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma from Japan MHLW. [2]. Shimizu J, Kawano F. Exercise-induced histone H3 trimethylation at lysine 27 facilitates the adaptation of skeletal muscle to exercise in mice. J Physiol. 2022 Jul;600(14):3331-3353. [3]. Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. Cell Rep. 2019 Nov 19;29(8):2321-2337.e7. |
| Additional Infomation | Valemetostat is an orally available selective inhibitor of the histone lysine methyltransferases enhancer of zeste homolog 1 (EZH1) and 2 (EZH2), with potential antineoplastic activity. Upon oral administration, valemetostat selectively inhibits the activity of both wild-type and mutated forms of EZH1 and EZH2. Inhibition of EZH1/2 specifically prevents the methylation of lysine 27 on histone H3 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and results in decreased proliferation of EZH1/2-expressing cancer cells. EZH1/2, histone lysine methyltransferase (HMT) class enzymes and catalytic subunits of the polycomb repressive complex 2 (PRC2), are overexpressed or mutated in a variety of cancer cells and play key roles in tumor cell proliferation, progression, stem cell self-renewal and migration. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~70 mg/mL (~143.44 mM) |
| 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. 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |