Herein, we describe thediscovery of novel compounds using structure-based drug design toswitch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitorsto an MTA-cooperative binding mechanism by occupying the portion ofthe SAM binding pocket in PRMT5 that is unoccupied when MTA is boundand hydrogen bonding to Arg368, thereby allowing them to selectivelytarget MTAP-deleted cancer cells. This evidence concerns the gene PRMT5 and cancer.