molecules of the month

The Janssen PRMT5 inhibitor, onametostat (JNJ-64619178) is a selective, orally active and pseudo-irreversible protein arginine methyltransferase 5 (PRMT5) inhibitor with high selectivity and potency (subnanomolar range, PRMT5-MEP-50 IC50=0.14 nM) under various conditions. While JNJ-64619178 binds non-covalently in the PRMT5 SAM and substrate-binding sites evidenced by co-crystallography (PDB: 6RLQ), the molecule has a long-residence time, leading to sustained inhibition of PRMT5 even after short compound exposure. Interestingly, PD was observed for 6 days after treatment cessation, and comparable efficacy was observed with continuous daily dosing as in 7 d on, 7 d off cycles. Since PRMT5-dependent methylation events are reversed only by turnover of substrate proteins rather than by demethylases and PRMT5 itself has a long half-life, PRMT5 inhibitors with a long residence time…