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| Targets |
EZH2-IN-15 specifically targets the catalytic SET domain of EZH2, the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). As a SAM-competitive inhibitor, it competes with the cofactor S-adenosylmethionine to inhibit the methyltransferase activity of EZH2. This inhibition reduces histone H3 lysine 27 trimethylation (H3K27me3), thereby reversing aberrant gene silencing that promotes cancer cell growth.
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| ln Vitro |
EZH2-IN-15 demonstrates sub-nanomolar inhibitory potency against wild-type EZH2 methyltransferase activity with an IC₅₀ of 0.87 nM as measured by CTG assay. In cellular models, it reduces the level of histone H3K27me3, induces cell apoptosis, alters cell cycle progression, and downregulates cell cycle-related proteins. Compared to EPZ-6438 (tazemetostat), SHR2554 presented comparable anti-tumor activity in vitro and showed high sensitivity. The compound has shown significant effects on T-cell lymphoma research models.
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| ln Vivo |
In vivo, EZH2-IN-15 has demonstrated anti-tumor activity in preclinical studies for H3K27me3-dependent tumors. Its oral bioavailability supports its use in animal models. The compound has advanced to clinical studies, indicating promising in vivo efficacy and tolerability. In a Phase 2 study, SHR2554 (350 mg twice daily) demonstrated significant and clinically meaningful improvements in patients with relapsed or refractory PTCL.
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| Enzyme Assay |
The enzymatic inhibitory activity of EZH2-IN-15 is assessed using biochemical assays with recombinant wild-type EZH2 enzyme. The compound's potency is typically measured by its ability to inhibit the methylation of a peptide substrate, with IC₅₀ values determined from dose-response curves.
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| Cell Assay |
Cell-based assays for EZH2-IN-15 involve treating cancer cell lines and measuring H3K27me3 levels by Western blotting or ELISA. The compound's effects on cell apoptosis, cell cycle progression, and the expression of cell cycle-related proteins are assessed using flow cytometry and immunoblotting. Its antiproliferative activity is quantified using CTG assays.
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| Animal Protocol |
In vivo studies for EZH2-IN-15 are conducted in mouse xenograft models of H3K27me3-dependent tumors. The compound is typically administered orally. Tumor growth inhibition is monitored, and pharmacodynamic markers such as H3K27me3 levels in tumor tissues are assessed to confirm target engagement.
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| ADME/Pharmacokinetics |
EZH2-IN-15 is orally bioavailable. Detailed pharmacokinetic parameters such as half-life and Cmax are available from the clinical studies conducted for this compound. The compound is formulated for oral administration in preclinical and clinical settings.
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| Toxicity/Toxicokinetics |
EZH2-IN-15 has been evaluated in first-in-human Phase 1 and Phase 2 clinical studies for hematological malignancies. In a Phase 2 study, SHR2554 (350 mg twice daily) demonstrated significant and clinically meaningful improvements in patients with relapsed or refractory PTCL, leading to its approval in China. The compound is generally well-tolerated at therapeutic doses.
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| References | |
| Additional Infomation |
EZH2-IN-15 (SHR2554) is a clinical-stage, oral EZH2 inhibitor that has progressed beyond preclinical proof-of-concept and received regulatory approval in China. It is a valuable tool for studying H3K27me3-dependent tumors and has therapeutic applications in hematological malignancies. The combination of SHR2554 with histone deacetylase inhibitors has shown dramatic antitumor activity in diffuse large B-cell lymphoma (DLBCL).
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| Molecular Formula |
C32H44N4O4
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|---|---|
| Molecular Weight |
548.7162
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| Exact Mass |
548.336
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| CAS # |
2098545-98-1
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| PubChem CID |
135332280
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| Appearance |
Off-white to yellow solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
40
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| Complexity |
968
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N(C([H])([H])C([H])([H])[H])C1=C([H])C2=C(C([H])=C(C([H])([H])N3C([H])([H])C([H])([H])C([H])([H])C([H])([H])C3([H])[H])O2)C(C(N([H])C([H])([H])C2C(N([H])C(C([H])([H])[H])=C([H])C=2C([H])([H])[H])=O)=O)=C1C([H])([H])C([H])([H])[H]
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| InChi Key |
YLZVNQZYAYVUCW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H44N4O4/c1-5-25-28(36(6-2)23-10-14-39-15-11-23)18-29-26(17-24(40-29)20-35-12-8-7-9-13-35)30(25)32(38)33-19-27-21(3)16-22(4)34-31(27)37/h16-18,23H,5-15,19-20H2,1-4H3,(H,33,38)(H,34,37)
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| Chemical Name |
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-(piperidin-1-ylmethyl)-1-benzofuran-4-carboxamide
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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 (~227.80 mM)
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|---|---|
| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8224 mL | 9.1121 mL | 18.2242 mL | |
| 5 mM | 0.3645 mL | 1.8224 mL | 3.6448 mL | |
| 10 mM | 0.1822 mL | 0.9112 mL | 1.8224 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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