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Information
EED226 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.
Targets
EED ; PRC2 82 nM(Kd); 114 nM(Kd)
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 Research(from reference)
Cell lines：G401 cells
Concentrations：0.12, 0.37, 1.1, 3.3, 10 μM
Incubation Time：3 d
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Ver folha de especificações →Taxonomy Tree
| Kingdom | Organic compounds |
|---|---|
| Superclass | Organoheterocyclic compounds |
| Classe | Triazolopyrimidines |
| Subclass | Not available |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Triazolopyrimidines |
| Alternative Parents | Benzenesulfonyl compounds Secondary alkylarylamines Aminopyrimidines and derivatives Triazoles Sulfones Heteroaromatic compounds Furans Oxacyclic compounds Azacyclic compounds Organopnictogen compounds Organooxygen compounds Organic oxides Hydrocarbon derivatives |
| Molecular Framework | Aromatic heteropolycyclic compounds |
| Substituents | Benzenesulfonyl group - Triazolopyrimidine - Secondary aliphatic/aromatic amine - Aminopyrimidine - Benzenoid - Pyrimidine - Monocyclic benzene moiety - Heteroaromatic compound - 1,2,4-triazole - Triazole - Sulfonyl - Sulfone - Furan - Azole - Oxacycle - Azacycle - Secondary amine - Organic nitrogen compound - Organic oxygen compound - Organopnictogen compound - Organic oxide - Hydrocarbon derivative - Organosulfur compound - Organooxygen compound - Organonitrogen compound - Amine - Aromatic heteropolycyclic compound |
| Descrição | This compound belongs to the class of organic compounds known as triazolopyrimidines. These are polycyclic aromatic compounds containing triazole ring fused to a pyrimidine ring. Triazole is a five-membered ring consisting of two carbon atoms and three nitrogen atoms. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions. |
| External Descriptors | Not available |
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| Solubilidade | Solubility (25°C) In vitro DMSO: 73 mg/mL warmed with 50ºC Water: bath (197.61 mM); Water: Insoluble; Ethanol: Insoluble; |
|---|---|
| DMSO (mg/mL) Solubilidade máxima | 73 |
| DMSO (mM) Solubilidade máxima | 197.6177585 |
| Água (mg/mL) Solubilidade máxima | ＜1 |
| Peso molecular | 369.400 g/mol |
| XLogP3 | 2.300 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Exact Mass | 369.09 Da |
| Monoisotopic Mass | 369.09 Da |
| Topological Polar Surface Area | 111.000 Ų |
| Heavy Atom Count | 26 |
| Formal Charge | 0 |
| Complexity | 575.000 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| The total count of all stereochemical bonds | 0 |
| Covalently-Bonded Unit Count | 1 |
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