In vitro: EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. It regulates histone H3K27 methylation and PRC2 target gene expression in cells. In the in vitro enzymatic assays, EED226 inhibits PRC2 with an IC50 (half-maximal inhibitory concentration) of 23.4 nM when the H3K27me0 peptide is used as substrate and an IC50 of 53.5 nM when the mononucleosome is used as the substrate, with the stimulatory H3K27me3 added at 1 × Kact (1.0 μM). EED226 is noncompetitive with both SAM and peptide substrate. EED226 bound to EED and PRC2 complex with a 1:1 stoichiometry and Kd of 82 nM and 114 nM, respectively. EED226 does not disrupt the PRC2 complex and could still occupy its binding pocket with a SAM-competitive EZH2 inhibitor bound to PRC2. EED226 shows remarkable selectivity for PRC2 complex over 21 other protein methyltransferases, kinases and other protein classes, The only other histone methyltransferase that can be inhibited by EED226 is the EZH1-PRC2 complex. EED226 with moderate permeability leads to a dose-dependent decrease of both global H3K27me3 and H3K27me2 markers in G401 cell. In vivo: EED226 effectively induces tumor regression in a mouse xenograft model. EED226 in a solid dispersion formulation are well tolerated in animals. EED226 clearly demonstrates a dose-dependent efficacy in the mouse xenograph study. EED226 inhibits the growth of diffuse large B-cell lymphoma (DLBCL) xenografts and reduces H3K27me3 levels to a similar extent as an EZH2 inhibitor. EED226 has very low in vivo and in vitro clearance and approximately 100% oral bioavailability, low volume of distribution (0.8 L/kg), reasonable terminal t1/2 (2.2 h), and moderate plasma protein binding (PPB)(14.4%). Its solubility is relatively low and with little dependency on the pH of the medium.
| Cell Experiment | |
|---|---|
| Cell lines | G401 cells |
| Preparation method | G401 cells are treated with EED226 for 3 d at the indicated concentrations. Total histone H3 is shown as a loading control. WB analysis for protein expression of H3K27me3, H3K27me2, H3K27me1. |
| Concentrations | 0.12, 0.37, 1.1, 3.3, 10 μM |
| Incubation time | 3 d |
| Animal Experiment | |
|---|---|
| Animal models | Karpas422 xenograft tumors (mouse model) |
| Formulation | 75% Soluplus + 5% sodium laureth sulfate + 20% EED226 |
| Dosages | 10 ml/kg |
| Administration | oral administration |
| Molecular Weight | 369.40 |
| Formula | C17H15N5O3S |
| CAS Number | 2083627-02-3 |
| Solubility (25°C) | 73 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related PRC2/EED Products |
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ORIC-944 is a selective, orally active, allosteric inhibitor targeting the EED subunit of polycomb repressive complex 2 (PRC2). ORIC-944 is synergistic with androgen receptor pathway inhibitors (ARPIs) for the study of metastatic prostate cancer. |
| EEDi-5285
Eedi-5285 is a highly effective and orally active inhibitor of embryonic ectodermal development (EED). The IC50 value of BINDING EED protein is 0.2 nM, and it has anticancer activity. |
| EEDi-5273
Eedi-5273 is a potent and orally effective EED inhibitor (IC50 = 0.2 nM) that can achieve complete and sustained tumor regression. |
| A-395
A-395 is A Polycomb inhibitory complex 2 (Polycomb repressive complex 2; PRC2), a protein-protein interaction antagonist, inhibits the trimer PRC2 complex (ezh2-EED -SUZ12) with an IC50 value of 18 nM. |
| FTX-6058
FTX-6058 is a potent, orally active embryonic ectodermal development (EED) inhibitor. FTX-6058 can induce HbF protein expression in both cell and murine models. FTX-6058 can be used in the study of specific hemoglobinopathies, including sickle cell disease and β-thalassemia. |
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