EPZ011989 trifluoroacetate is a potent, selective orally bioavailable EZH2 inhibitor with Ki < 3 nM for EZH2 wt and EZH2 Y646; 15-fold selectivity over EZH1 and >3000-fold selectivity over other HMTase. IC50 value: < 3 nM ( Ki for wt EZH2, EZH2 Y646) Target: EZH2 inhibitor In vitro: EPZ011989 is also a specific EZH2 inhibitor with a >15-fold selectivity over EZH1 and >3000-fold selectivity relative to the Ki of 20 other histone methyltransferases (HMTs) tested. EPZ011989 also exhibits metabolic stability. Furthermore, EPZ011989 reduces cellular H3K27 methylation in the Y641F, mutant-bearing human lymphoma cell line, WSU-DLCL2, with an IC50 below 100 nM. This functional response translates to activity in a long-term proliferation assay where EPZ011989 demonstrates an average lowest cytotoxic concentration (LCC) in WSU-DLCL2 cells of 208 nM. In vivo: The LCC parameter, when corrected for plasma protein-binding, predicts an efficacious plasma level in mouse for EPZ011989 of 158 ng/mL. The pharmacokinetics in SCID mice following oral administration of 125, 250, 500, and 1000 mg/kg indicated that the 1000 mg/kg dose provided coverage over the LCC for 24 h, while the 250 and 500 mg/kg doses provided coverage over this value for approximately 8 h. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma.
| Molecular Weight | 719.83 |
| CAS Number | 1598383-41-5 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage | 2-8°C, dry, sealed |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Histone Methyltransferase Products |
|---|
| SAH-EZH2
SAH-EZH2, a stable EZH2 α-helical peptide, is an EZH2/EED interaction inhibitor. |
| UNC4976
UNC4976 is a positive allosteric modulator (PAM) peptidomimetic of CBX7 chromodomain binding to nucleic acids. |
| C21
C21 is a potent, irreversible, and selective PRMT1 inhibitor with an IC50 of 1.8 μM. |
| EZH2-IN-15
EZH2-IN-15 (SHR2554) is a EZH2 inhibitor. |
| NSD-IN-2
NSD-IN-2 is a potent and irreversible NSD1 inhibitor. |
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