Biological Activity
EPZ015666 is an orally available inhibitor of PRMT5 with an IC50 of 22 nM.
In Vitro
Treatment of MCL cell lines with EPZ015666 leads to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range[1]. EPZ015666, a potent peptide-competitive and SAM-cooperative inhibitor with >10,000-fold specificity against PRMT5 relative to other methyltransferases[2].
In Vivo
EPZ015666 is orally bioavailable and amenable to in vivo studies. We performed 21-d efficacy studies in severe combined immunodeficiency (SCID) mice bearing subcutaneous Z-138 and Maver-1 xenografts, with twice-daily (BID) oral dosing on four dose groups: 25, 50, 100 and 200 mg per kilogram of body weight (mg/kg). After 21 d of continuous dosing, animals are euthanized, and blood and tissues are analyzed to determine the relationship between methyl-mark pharmacodynamics and tumor-growth inhibition (TGI). EPZ015666 showed dose-dependent exposure and TGI after 21 d in both MCL models. Tumors in all EPZ015666 dose groups measured on day 21 showed statistically significant differences in weight, volume and tumor growth compared to vehicle-treated tumors. Dosing at 200 mg/kg BID induced tumor stasis in Z-138 cells, with >93% TGI after 21 d, whereas Maver-1 cells showed >70% TGI. Additionally, a third MCL xenograft is tested using the Granta-519 cell line, a fast-growing model that reached endpoint on day 18 and showed dose-dependent efficacy with 45% TGI in the 200 mg/kg group. EPZ015666 is well tolerated in all three models, with minimal bodyweight loss in the 200 mg/kg dose group and no other clinical observations[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
