YM-281 is a novel VHL-Based PROTAC degrader of EZH2 with anticancer activity. It can induce cell apoptosis and cell cycle arrest at the G0/G1 phase. YM281 has the potential to be used for the treatment of lymphoma.
Physicochemical Properties
| Molecular Formula | C56H71N7O9S |
| Molecular Weight | 1018.27 |
| Exact Mass | 1017.503 |
| CAS # | 2230914-84-6 |
| PubChem CID | 135147352 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 7 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 12 |
| Rotatable Bond Count | 21 |
| Heavy Atom Count | 73 |
| Complexity | 1940 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | CCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)OCCCOCC(=O)N[C@H](C(=O)N5C[C@@H](C[C@H]5C(=O)NCC6=CC=C(C=C6)C7=C(N=CS7)C)O)C(C)(C)C |
| InChi Key | HBGYJNIDFUPUJQ-DDGSYWGGSA-N |
| InChi Code | InChI=1S/C56H71N7O9S/c1-9-62(42-19-23-70-24-20-42)47-27-41(26-45(36(47)4)52(66)58-30-46-34(2)25-35(3)60-53(46)67)39-15-17-44(18-16-39)72-22-10-21-71-32-49(65)61-51(56(6,7)8)55(69)63-31-43(64)28-48(63)54(68)57-29-38-11-13-40(14-12-38)50-37(5)59-33-73-50/h11-18,25-27,33,42-43,48,51,64H,9-10,19-24,28-32H2,1-8H3,(H,57,68)(H,58,66)(H,60,67)(H,61,65)/t43-,48+,51-/m1/s1 |
| Chemical Name | (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methylcarbamoyl]-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl]phenoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide |
| 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 | Via the VHL (vonHippel−Lindau)-dependent ubiquitin-proteasome system, YM281 (compound V2) (0-6 µM; 0-48 h) reduces the EZH2 protein level and the PRC2 (polycomb repressive complex 2) complex[1]. In lymphoma cells, YM281 (0–10 µM; 24 h) has anticancer properties[1]. Cell death and cell cycle arrest are induced by YM281 (0-5 µM) at the G0/G1 phase[1]. YM281 (0–5 µM; 24 h) decreases primary lymphoma cell viability while increasing caspase-3 and -7 activity[1]. |
| ln Vivo | YM281 (80, 100 mg/kg; intravenously; six times over three weeks) has anticancer effects and dramatically lowers H3K27me3 levels and EZH2 protein expression[1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: SU-DHL-2, 22Rv1 cells Tested Concentrations: 0-6 µM Incubation Duration: 0-48 h Experimental Results: Abrogated both the EZH2 protein level and the H3K27me3 degree in a concentration-dependent manner in 24 h, had no significant effect on the protein level of EZH1, and Dramatically increased the expression of EZH2 ubiquitination. Cell Viability Assay[1] Cell Types: SU-DHL-2, SU-DHL-4, SU-DHL-6 cells Tested Concentrations: 0-10 µM Incubation Duration: 24 h Experimental Results: Induced nearly complete cell viability inhibition. Cell Cycle Analysis[1] Cell Types: SU-DHL-6 cells Tested Concentrations: 1, 3, 5 µM Incubation Duration: 24 h Experimental Results: Induced cell cycle arrest at the G0/G1 phase and a profound sub-G1 population increase in a concentration-dependent manner. Apoptosis Analysis[1] Cell Types: SU-DHL-6 cells Tested Concentrations: 0-5 µM Incubation Duration: 48 h Experimental Results: Dramatically increased the expression of cleaved caspase-3 and PARP. |
| Animal Protocol |
Animal/Disease Models: Balb/c nude mice (SU-DHL-6 xenograft model)[1] Doses: 80 mg/kg Route of Administration: Iv; 6 times for 3 weeks Experimental Results: Remarkably suppressed the tumor volume and Dramatically decreased the EZH2 protein and H3K27me3 levels. Animal/Disease Models: Balb/c nude mice (Jeko-1 xenograft model)[1] Doses: 100 mg/kg Route of Administration: Iv; 6 times for 3 weeks Experimental Results: Shows anti-tumor effects with the Dramatically decreased the expression of EZH2 protein and H3K27me3 levels. |
| References | [1]. Tu Y,et al. Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma. J Med Chem. 2021 Jul 22;64(14):10167-10184. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9821 mL | 4.9103 mL | 9.8206 mL | |
| 5 mM | 0.1964 mL | 0.9821 mL | 1.9641 mL | |
| 10 mM | 0.0982 mL | 0.4910 mL | 0.9821 mL |