Chengdu Henghui Pharmaceutical Co., Ltd.(expird)
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EPZ015666 is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with IC50 of 22 nM and broad selectivity against a panel of other histone methyltransferases.Treatment of MCL cell lines with EPZ015666 leads to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. EPZ015666, a potent peptide-competitive and SAM-cooperative inhibitor with >10,000-fold specificity against PRMT5 relative to other methyltransferases.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.