EED226

製品コードS8496 バッチS849601

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C17H15N5O3S
分子量 369.40 CAS No. 2083627-02-3
Solubility (25°C)* 体外 DMSO 73 mg/mL warmed with 50ºC water bath (197.61 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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.
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[1].
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[1]. EED226 inhibits the growth of diffuse large B-cell lymphoma (DLBCL) xenografts and reduces H3K27me3 levels to a similar extent as an EZH2 inhibitor[2]. 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[3].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 G401 cells
濃度 0.12, 0.37, 1.1, 3.3, 10 μM
反応時間 3 d
実験の流れ

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.
動物実験 動物モデル Karpas422 xenograft tumors (mouse model)
投薬量 10 ml/kg
投与方法 oral administration

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming [ Elife, 2023, 12e85365] PubMed: 37698486
Inhibition of EED activity enhances cell survival of female germline stem cell and improves the oocytes production during oogenesis in vitro [ Open Biol, 2023, 13(1):220211] PubMed: 36695089
Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery [ Nat Commun, 2022, 13(1):4199] PubMed: 35859152
Ezh2 competes with p53 to license lncRNA Neat1 transcription for inflammasome activation [ Cell Death Differ, 2022, 10.1038/s41418-022-00992-3] PubMed: 35568718
PRC2-mediated epigenetic suppression of type I IFN-STAT2 signaling impairs antitumor immunity in luminal breast cancer [ Cancer Res, 2022, CAN-22-0736] PubMed: 36222718
Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer [ Cell Death Dis, 2022, 13(2):155] PubMed: 35169119
Inhibition of polycomb repressive complex 2 by targeting EED protects against cisplatin-induced acute kidney injury [ J Cell Mol Med, 2022, 26(14):4061-4075] PubMed: 35734954
EZH2-mediated H3K27me3 is a predictive biomarker and therapeutic target in uveal melanoma [ Front Genet, 2022, 13:1013475] PubMed: 36276954
PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia [ Cancer Discov, 2021, candisc.1771.2020] PubMed: 34417224
Loss of PRC2 subunits primes lineage choice during exit of pluripotency [ Nat Commun, 2021, 12(1):6985] PubMed: 34848733

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人間や獣医の診断であるか治療的な使用のためにでない。

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