PRMT5 inhibitor 16-19F is a specific synthetic inhibitor of the PRMT5-MTA complex with SPR KD of 2.54, 0.36 and 0.15 uM against apo-PRMT5:MEP50 and SAM- and MTA-bound PRMT5:MEP50 complexes respectively, selectively inhibits MTAP-deleted cancer cell growth.
16-19F preferentially binds to and stabilizes the catalytically inactive PRMT5·MTA complex, which would inhibit PRMT5 activity in MTAP–/– cells while preserving PRMT5 activity in MTAP+ cells.
16-19F demonstrates potent selectivity to MTAP–/– cancer cell lines with IC50 values of 17.8 and 15.7 μM in MDA-MB-231 and MIA PaCa-2, compared to IC50 >100 μM in MDA-MB-435s cells, which SAM-cooperative inhibitor (GSK3326595) shows little cell viability inhibition.
16-19F strongly inhibited PRMT5 coimmunoprecipitated MCM7 sDMA compared to GSK3326595.
16-19F binds to the PRMT5•MTA, PRMT5•SAH, and PRMT5•SAM complexes and selectively inhibited MTAP-deleted cancer cell growth.