In vitro activity: EPZ015666 (also known as GSK3235025, an analog of EPZ015866) is a potent, selective and orally bioavailable inhibitor of PRMT5 (protein arginine methyltransferase) enzymatic activity in biochemical assays with Ki of 5-22 nM, and shows>20,000-fold selectivity over other PMTs. EPZ015666 demonstrates broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

Kinase Assay: EPZ015666 (also known as GSK3235025, an analog of EPZ015866) is a potent, selective and orally bioavailable inhibitor of PRMT5 (protein arginine methyltransferase) enzymatic activity in biochemical assays with Ki of 5-22 nM, and shows>20,000-fold selectivity over other PMTs. EPZ015666 demonstrates broad selectivity against a panel of other histone methyltransferases.

Cell Assay: EPZ015666 shows potent cellular activity that blocks symmetric dimethylation of SmD3 and inhibit proliferation of MCL cell lines (Z-138, Granta-519, Maver-1, Mino, and Jeko-1) with IC50 of 96-904 nM. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range.