Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

PRMT5
is a major type II protein arginine methyltransferase and
plays important roles in diverse cellular processes. Overexpression
of PRMT5 is implicated in various types of cancer. Many efforts have
been made to develop potent and selective PRMT5 inhibitors, the most
potent of which is usually derived from nucleoside structures. Here,
we designed a novel series of non-nucleoside PRMT5 inhibitors through
the structure-aided drug design approach. SAR exploration and metabolic
stability optimization led to the discovery of compound 41 as a potent PRMT5 inhibitor with good selectivity. Additionally,
compound 41 exerted antiproliferative effects against
A375 cells by inducing apoptosis and potently inhibited the methyltransferase
activity of PRMT5 in cells. Moreover, it showed attractive pharmacokinetic
properties and markedly suppressed the tumor growth in an A375 tumor
xenograft model. These results clearly indicate that 41 is a highly potent and selective non-nucleoside PRMT5 inhibitor.