N1,N2-Dimethyl-N1-[[3-[4-[[trans-3-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]cyclobutyl]oxy]phenyl]-1H-pyrazol-4-yl]methyl]-1,2-ethanediamine hydrochloride

Biological Activity

EPZ020411 hydrochloride is a potent and selective small molecule inhibitor of PRMT6 with IC50 of 10 nM.

in vitro

EPZ020411 hydrochloride dose-dependently reduced H3R2 methylation in human melanoma A375 cells overexpressing PRMT6 (IC50=0.637±0.241 μM). In biochemical assays, the selectivity of EPZ020411 to PRMT6/8/1 was more than 100-fold higher than that of other histone methyltransferases (including 4 arginine methyltransferases PRMT3, PRMT4, PRMT5, PRMT7). In the parallel artificial membrane permeation test, EPZ020411 has poor permeability.

in vivo

EPZ020411 hydrochloride has good bioavailability in rats by subcutaneous injection and is a suitable compound for in vivo studies. After a single intravenous injection of 1 mg/kg EPZ020411 hydrochloride into male Sprague-Dawley rats, its in vivo clearance (CL) was 19.7 ± 1.0 mL/min/kg and its volume of distribution at steady state (Vss) was 11.1 ± 1.6 L/kg, the average half-life was 8.54±1.43 h. Subcutaneous injection of 5 mg/kg has good bioavailability of 65.6 ± 4.3%, and the free concentration of EPZ020411 in the blood is higher than the biochemical IC50 value of PRMT6 for more than 12 hours.

target

< td style="border-bottom: 1px dotted #ccc;padding: 5px;"> PRMT8
(Cell-free assay)

Target	Value
PRMT6 (Cell-free assay)	10 nM
PRMT1 (Cell-free assay)	119 nM
223 nM