EPZ020411

EPZ020411 is not greatly selective for PRMT6 over PRMT1 or PRMT8 in vitro. PRMT6 is the only PRMT known to methylate the H3R2 position, and EPZ020411 can be used as a probe to assess the functionality of this post-translational modification. While this compound shows poor bioavailability following oral dosing (<5%), subcutaneous (SC) dosing results in significant plasma levels, making this compound suitable for in vivo studies of the H3R2 mark using SC dosing.

Selectivity over some other isoforms of arginine methyltransferase is limited 10 - 20 fold. No data is available on CNS exposure of EPZ02041.

EPZ020411 is a potent inhibitor of PRMT6 in biochemical (IC₅₀ = 10 nM) and cellular (IC₅₀ = 600 nM) assays EPZ020411 is selective against the related enzymes PRMT3, PRMT4, PRMT5, and PRMT7 in a biochemical assay, and relatively selective against PRMT1 and PRMT8, in biochemical (IC₅₀'s = 100 and 200 nM, respectively) and cellular assays (for PRMT1). Even though EPZ020411 is selective within the PRMT family, there is no information on other relevant human methyltransferases. (See 10.1021/acs.jmedchem.5b01772  and 10.1021/acschembio.5b00839 for examples of PRMT6 inhibitors profiled vs. other methyltransferases). In vivo EPZ020411 is 65% bioavailable following 5 mg/kg s.c. administration. Unfortunately, the unbound blood concentration of EPZ020411 is above the H3R2-methylation IC₅₀ (cellular assay) for less than 6h. Additional studies will be required to define if this exposure is enough for a relevant pharmacological effect in vivo.