MS115 TFA

MS115 TFA is a selective PRMT5/MEP50 PROTAC degrader with DC50 values of 17.4 nM for PRMT5 and 11.3 nM for MEP50 after 24 hours in MDAMB468 cells. It inhibits the proliferation of breast cancer cells.

MS115 (TFA form) at a concentration of 2.1 μM for 120 minutes effectively inhibits PRMT5 methyltransferase activity in cell-free assays, achieving an IC50 of 2.1 μM. In MDAMB468 cells, MS115 at 0.01-5 μM for 3-72 hours degrades PRMT5 (DC50: 17.4 nM) and MEP50 (DC50: 11.3 nM) with over 85% maximum degradation in a concentration and time-dependent manner. For mechanism assays, MS115 at 0.5-5 μM for 24-72 hours, with 1-2 hours pretreatment, induces PRMT5/MEP50 degradation through binding with PRMT5 and VHL, mediated by the ubiquitin-proteasome system. Cell proliferation in MDAMB468 is inhibited by MS115 (serial dilutions; 7 days) with a gIC50 of 5.6 μM. Similarly, MS115 (serial dilutions; 5 days) inhibits proliferation of breast cancer cells MDAMB453, MDAMB231, and MCF7, comparable to PRMT5 inhibitor GSKi. In PC-3 prostate cancer cells, MS115 (0.004-5 μM; 7 hours to 3 days) shows more efficient PRMT5/MEP50 degradation than MS4322, a known PRMT5 degrader. For normal epithelial cells, MS115 (0.5-5 μM; 3 days) degrades PRMT5/MEP50 in MCF10A and PNT2 without significant cytotoxicity and also degrades PRMT5/MEP50 in these normal cell lines (MCF10A, PNT2) with serial dilutions over 5-6 days.

MS115 TFA (50 mg/kg; intraperitoneal injection; single dose) demonstrates favorable pharmacokinetic properties in mice, as it is rapidly absorbed and maintains sustained plasma exposure levels following a single intraperitoneal administration of 50 mg/kg.