Home Epigenetics DNA/RNA Synthesis inhibitor EED226

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EED226 DNA/RNA Synthesis inhibitor

Cat.No.S8496

EED226 is a potent, selective, and orally bioavailable a novel allosteric Polycomb repressive complex 2 (PRC2) inhibitor with an IC50 of 23.4 nM when the H3K27me0 peptide was used as substrate and an IC50 of 53.5 nM when the mononucleosome was used as the substrate. It directly binds to the H3K27me3 binding pocket of EED.
EED226 DNA/RNA Synthesis inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 369.40

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Quality Control

Batch: S849601 DMSO]73 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.93%
99.93

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
KARPAS422 Antiproliferative assay up to 14 days Antiproliferative activity against human KARPAS422 cells harboring monoallelic Y641N EZH2 mutation assessed as reduction in cell viability measured every 3 to 4 days up to 14 days by Beckman Coulter-based method, IC50 = 0.08 μM. 28092155
G401 Function assay 48 hrs Inhibition of EED in human G401 cells assessed as reduction in global H3K27me3 level after 48 hrs by ELISA, IC50 = 0.22 μM. 28092155
KARPAS422 Antitumor assay 300 mg/kg 34 days Antitumor activity against human KARPAS422 cells xenografted in Balb/C nude mouse assessed as tumor regression at 300 mg/kg, po BID for 34 days 28092155
KARPAS422 Antitumor assay 1.5 to 40 mg/kg 2 weeks Antitumor activity against human KARPAS422 cells xenografted in Balb/C nude mouse assessed as reduction in tumor volume at 1.5 to 40 mg/kg, po BID for 2 weeks 28092155
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 73 mg/mL (197.61 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 369.40 Formula

C17H15N5O3S

 Storage (From the date of receipt)
CAS No. 2083627-02-3 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CS(=O)(=O)C1=CC=C(C=C1)C2=CN=C(N3C2=NN=C3)NCC4=CC=CO4

Mechanism of Action

Targets/IC50/Ki
EED
82 nM(Kd)
PRC2
114 nM(Kd)
In vitro
EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. This compound 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, this chemical 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). It is noncompetitive with both SAM and peptide substrate. This compound bound to EED and PRC2 complex with a 1:1 stoichiometry and Kd of 82 nM and 114 nM, respectively. It does not disrupt the PRC2 complex and could still occupy its binding pocket with a SAM-competitive EZH2 inhibitor bound to PRC2. This chemical 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 it is the EZH1-PRC2 complex. It with moderate permeability leads to a dose-dependent decrease of both global H3K27me3 and H3K27me2 markers in G401 cell.
In vivo
This compound effectively induces tumor regression in a mouse xenograft model. It in a solid dispersion formulation are well tolerated in animals. This chemical clearly demonstrates a dose-dependent efficacy in the mouse xenograph study. It inhibits the growth of diffuse large B-cell lymphoma (DLBCL) xenografts and reduces H3K27me3 levels to a similar extent as an EZH2 inhibitor. It 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.
References

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