EED226
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MedKoo CAT#: 407382

CAS#: 2083627-02-3

Description: EED226 is a potent, selective, and orally bioavailable EED inhibitor. induces robust and sustained tumor regression in EZH2MUT preclinical DLBCL model. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers. demonstrated very impressive antitumor activities in mouse xenograft model.


Chemical Structure

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EED226
CAS# 2083627-02-3

Theoretical Analysis

MedKoo Cat#: 407382
Name: EED226
CAS#: 2083627-02-3
Chemical Formula: C17H15N5O3S
Exact Mass: 369.0896
Molecular Weight: 369.399
Elemental Analysis: C, 55.28; H, 4.09; N, 18.96; O, 12.99; S, 8.68

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 850.0 Same day
500.0mg USD 1650.0 Same day
1.0g USD 2650.0 2 weeks
2.0g USD 4650.0 2 weeks
5.0g USD 8950.0 2 weeks
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Synonym: EED226; EED-226; EED 226.

IUPAC/Chemical Name: N-(Furan-2-ylmethyl)-8-(4-(methylsulfonyl)phenyl)[1,2,4]-triazolo[4,3-c]pyrimidin-5-amine

InChi Key: DYIRSNMPIZZNBK-UHFFFAOYSA-N

InChi Code: InChI=1S/C17H15N5O3S/c1-26(23,24)14-6-4-12(5-7-14)15-10-19-17(22-11-20-21-16(15)22)18-9-13-3-2-8-25-13/h2-8,10-11H,9H2,1H3,(H,18,19)

SMILES Code: O=S(C1=CC=C(C2=CN=C(NCC3=CC=CO3)N4C2=NN=C4)C=C1)(C)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: EED226 is a polycomb repressive complex 2 (PRC2) inhibitor, which binds to the K27me3-pocket on embryonic ectoderm development (EED).
In vitro activity: The basal expression of PRC2-related proteins was determined in HK1, C17C, NPC43 and C666-1 cell lines, with an immortalized epithelial nasopharyngeal epithelial cell line NP69 serving as a control. EZH2 and EED are expressed in all 4 NPC cell lines, while the expression levels of EZH2 and EED in EBV-positive NPC cell lines (C17C, NPC43 and C666-1) appeared to be higher than in the EBV-negative NPC cell lines (HK1) and NP69 cells (Figure 1C). Following treatment with EED226 at 1 μM, 5 μM and 10 μM for up to 72 hours, H3K27me3 expression was significantly reduced in both C666-1 and HK1 cell lines in a dose-response relationship (Figure 1D). EED226 could significantly reduce EED expression, but the effect on EZH2 was relatively modest (Figure 1E). Using proliferating cell nuclear antigen (PCNA) as an indicator, EED226 at low concentrations could inhibit cellular proliferation in C666-1 cells, while higher concentrations of EED226 were needed to inhibit proliferation in HK1 cells (Figure 1F). Reference: Am J Cancer Res. 2020; 10(10): 3267–3284. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642668/
In vivo activity: To further assess the effect of PRC2 inhibition by EED226 in vivo, 4 and 40 mg/kg twice-daily doses of EED226 were given to mice orally for a longer period of time, and tumor volume was measured. Both 4 and 40 mg/kg doses were well tolerated, and the 40 mg/kg dose induced complete tumor regression when dosed for 32 d (Fig. 4f,g and Supplementary Fig. 4c). In the 4 mg/kg bid dose group, tumor growth was also inhibited and reached stasis at the end of the dosing period (Fig. 4f). Thus, EED226 clearly demonstrates a dose-dependent efficacy in the mouse xenograph study. Reference: Nat Chem Biol. 2017 Apr;13(4):381-388. https://www.nature.com/articles/nchembio.2304

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 31.0 83.92
DMSO:PBS (pH 7.2) (1:1) 0.5 1.35
DMF 33.0 89.33

Preparing Stock Solutions

The following data is based on the product molecular weight 369.399 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Zhu J, Li L, Tong J, Hui C, Wong CH, Lo KW, Chan R, Ai QY, Hui EP, Chan AT, To KF, Tao Q, Ma BB. Targeting the polycomb repressive complex-2 related proteins with novel combinational strategies for nasopharyngeal carcinoma. Am J Cancer Res. 2020 Oct 1;10(10):3267-3284. PMID: 33163269; PMCID: PMC7642668. 2. Turner AW, Dronamraju R, Potjewyd F, James KS, Winecoff DK, Kirchherr JL, Archin NM, Browne EP, Strahl BD, Margolis DM, James LI. Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal. ACS Infect Dis. 2020 Jul 10;6(7):1719-1733. doi: 10.1021/acsinfecdis.9b00514. Epub 2020 May 30. PMID: 32347704; PMCID: PMC7359025. 3. Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, Zhang M, Zhang J, Yu Z, Li L, Teng L, Chuai S, Zhang C, Zhao M, Chan H, Chen Z, Fang D, Fei Q, Feng L, Feng L, Gao Y, Ge H, Ge X, Li G, Lingel A, Lin Y, Liu Y, Luo F, Shi M, Wang L, Wang Z, Yu Y, Zeng J, Zeng C, Zhang L, Zhang Q, Zhou S, Oyang C, Atadja P, Li E. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017 Apr;13(4):381-388. doi: 10.1038/nchembio.2304. Epub 2017 Jan 30. PMID: 28135235. 4. Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. J Med Chem. 2017 Mar 23;60(6):2215-2226. doi: 10.1021/acs.jmedchem.6b01576. Epub 2017 Feb 6. PMID: 28092155.
In vitro protocol: 1. Zhu J, Li L, Tong J, Hui C, Wong CH, Lo KW, Chan R, Ai QY, Hui EP, Chan AT, To KF, Tao Q, Ma BB. Targeting the polycomb repressive complex-2 related proteins with novel combinational strategies for nasopharyngeal carcinoma. Am J Cancer Res. 2020 Oct 1;10(10):3267-3284. PMID: 33163269; PMCID: PMC7642668. 2. Turner AW, Dronamraju R, Potjewyd F, James KS, Winecoff DK, Kirchherr JL, Archin NM, Browne EP, Strahl BD, Margolis DM, James LI. Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal. ACS Infect Dis. 2020 Jul 10;6(7):1719-1733. doi: 10.1021/acsinfecdis.9b00514. Epub 2020 May 30. PMID: 32347704; PMCID: PMC7359025.
In vivo protocol: 1. Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, Zhang M, Zhang J, Yu Z, Li L, Teng L, Chuai S, Zhang C, Zhao M, Chan H, Chen Z, Fang D, Fei Q, Feng L, Feng L, Gao Y, Ge H, Ge X, Li G, Lingel A, Lin Y, Liu Y, Luo F, Shi M, Wang L, Wang Z, Yu Y, Zeng J, Zeng C, Zhang L, Zhang Q, Zhou S, Oyang C, Atadja P, Li E. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017 Apr;13(4):381-388. doi: 10.1038/nchembio.2304. Epub 2017 Jan 30. PMID: 28135235. 2. Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. J Med Chem. 2017 Mar 23;60(6):2215-2226. doi: 10.1021/acs.jmedchem.6b01576. Epub 2017 Feb 6. PMID: 28092155.

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1: Targeting the EED-H3K27me3 Interaction Allosterically Inhibits PRC2. Cancer Discov. 2017 Feb 13. doi: 10.1158/2159-8290.CD-RW2017-030. [Epub ahead of print] PubMed PMID: 28193775.

2: Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, Zhang M, Zhang J, Yu Z, Li L, Teng L, Chuai S, Zhang C, Zhao M, Chan H, Chen Z, Fang D, Fei Q, Feng L, Feng L, Gao Y, Ge H, Ge X, Li G, Lingel A, Lin Y, Liu Y, Luo F, Shi M, Wang L, Wang Z, Yu Y, Zeng J, Zeng C, Zhang L, Zhang Q, Zhou S, Oyang C, Atadja P, Li E. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017 Apr;13(4):381-388. doi: 10.1038/nchembio.2304. Epub 2017 Jan 30. PubMed PMID: 28135235.

3: Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. J Med Chem. 2017 Mar 23;60(6):2215-2226. doi: 10.1021/acs.jmedchem.6b01576. Epub 2017 Feb 6. PubMed PMID: 28092155.

4: Li L, Zhang H, Zhang M, Zhao M, Feng L, Luo X, Gao Z, Huang Y, Ardayfio O, Zhang JH, Lin Y, Fan H, Mi Y, Li G, Liu L, Feng L, Luo F, Teng L, Qi W, Ottl J, Lingel A, Bussiere DE, Yu Z, Atadja P, Lu C, Li E, Gu J, Zhao K. Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED. PLoS One. 2017 Jan 10;12(1):e0169855. doi: 10.1371/journal.pone.0169855. eCollection 2017 Jan 10. PubMed PMID: 28072869; PubMed Central PMCID: PMC5224880.

EED226

25.0mg / USD 150.0


Additional Information

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3).