MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design

Deletion of the MTAP gene leads to accumulation
of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA
binds PRMT5 competitively with S-adenosyl-l-methionine (SAM),
and selective inhibition of the PRMT5•MTA complex relative
to the PRMT5•SAM complex can lead to selective killing of cancer
cells with MTAP deletion. Herein, we describe the
discovery of novel compounds using structure-based drug design to
switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors
to an MTA-cooperative binding mechanism by occupying the portion of
the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound
and hydrogen bonding to Arg368, thereby allowing them to selectively
target MTAP-deleted cancer cells.