product name EPZ005687
Description: EPZ005687 is a potent and selective inhibitor of EZH2 with Ki of 24 nM in a cell-free assay, 50-fold selectivity against EZH1 and 500-fold selectivity against 15 other protein methyltransferases. EPZ005687 concentration-dependently inhibits the enzymatic activity of PRC2 with a value of 50% inhibition concentration IC50 of 54 nM through binding to the S-adenosylmethionine (SAM) pocket of the EZH2 SET domain. Study results have shown that EPZ005687 reduces H3K27 methylation in a variety of lymphoma cells and induces apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells.
References: Nat Chem Biol. 2012 Nov;8(11):890-6.
539.67
Formula
C32H37N5O3
CAS No.
1396772-26-1
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 2 mg/mL (3.7 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: EPZ005687 shows concentration-dependent inhibition of PRC2 enzymatic activity with an IC50 value of 54 nM. It is a direct inhibitor of PRC2 enzymatic activity and does not function by disrupting the protein-protein interactions among the PRC2 subunits. EPZ005687 binds in the SAM pocket of the EZH2 SET domain and is a SAM-competitive inhibitor of EZH2 enzyme activity. The affinity of EPZ005687 is similar (within a two-fold range) for PRC2 complexes containing wild-type and Tyr641 mutant EZH2, but significantly greater affinity for the A677G mutant enzyme (5.4-fold). EPZ005687 reduces H3K27 methylation in various lymphoma cells. It shows robust cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. EPZ005687 increases G1 phase of the cell cycle with correlative decreases in the S as well as the G2/M phases. In a Tyr641 mutant lymphoma cell line, EPZ005687 can lead to derepression of known EZH2 target genes and affect genes specifically repressed by the EZH2 Tyr641 mutant. Kinase Assay: Compound is incubated for 30 min with 40 μL per well of 5 nM PRC2 (final assay concentration in 50 μL is 4 nM ) in 1X assay buffer (20 mM Bicine [pH 7.6], 0.002% Tween-20, 0.005% Bovine Skin Gelatin and 0.5 mM DTT). 10 μL per well of substrate mix comprising assay buffer 3 H-SAM, unlabeled SAM, and peptide representing histone H3 residues 21-44 containing C-terminal biotin (appended to a C-terminal amide-capped lysine) are added to initiate the reaction (both substrates are present in the final reaction mixture at their respective Km values, an assay format referred to as ‘‘balanced conditions’’. The final concentrations of substrates and methylation state of the substrate peptide are indicated for each enzyme Reactions are incubated for 90 min at room temperature and quenched with 10 μL per well of 600 μM unlabeled SAM, Then transferred to a 384-well flashplate and washed after 30 min. Cell Assay: EPZ005687 significantly inhibited the proliferation of WSU-DLCL2 and Pfeiffer cells, with minimal effects on the proliferation of OCI-LY19 cells. |
|---|---|
| In Vivo | Intra-articular injection of EPZ005687 delayed OA development in mice. |
| Animal model | Osteoarthritis (OA) mouse model |
| Formulation & Dosage | 5.6 μM, 50 μL; intra-articular injection |
| References | Nat Chem Biol. 2012 Nov;8(11):890-6; Sci Rep. 2016 Aug 19;6:29176. |
