MS115 TFA is a selective PRMT5/MEP50 PROTAC degrader, with DC50 values of 17.4 nM and 11.3 nM for PRMT5 and MEP50, respectively. MS115 TFA promotes PRMT5/MEP50 ubiquitination and degradation. MS115 TFA shows anticancer activity against breast cancer [1]. (Pink: PRMT5 and MEP50 ligand; Blue: VHL ligand; Black: linker).
In Vivo, MS115 (TFA) (50 mg/kg; i.p.; single dose) exhibits favorable mouse pharmacokinetic properties with rapid absorption and sustained plasma exposure following a single 50 mg/kg intraperitoneal injection[1].
In Vitro, MS115 (2.1 μM; 120 min) TFA inhibits PRMT5 methyltransferase activity in a cell-free assay with an IC50 of 2.1 μM[1]. MS115 (0.01-5 μM; 3-72 h) TFA potently and selectively degrades PRMT5 (DC50: 17.4 nM) and MEP50 (DC50: 11.3 nM) in MDAMB468 cells in concentration- and time-dependent manners, achieving >85% maximum degradation of both proteins[1]. MS115 (0.5-5 μM; 24-72 h, with 1-2 h pretreatment for mechanism assays) TFA mediates PRMT5/MEP50 degradation in MDAMB468 cells that requires binding to both PRMT5 and VHL, and proceeds via the ubiquitin-proteasome system[1]. MS115 (serial dilutions; 7 days) TFA inhibits MDAMB468 cell proliferation with a gIC50 of 5.6 μM[1]. MS115 (serial dilutions; 5 days) TFA inhibits proliferation of MDAMB453, MDAMB231, and MCF7 breast cancer cells, with potency comparable to the PRMT5 inhibitor GSKi[1]. MS115 (0.004-5 μM; 7 h-3 days) TFA potently degrades PRMT5/MEP50 in PC-3 prostate cancer cells, showing greater efficacy than the PRMT5 degrader MS4322[1]. MS115 (0.5-5 μM; 3 days) TFA degrades PRMT5/MEP50 in MCF10A normal breast epithelial cells and PNT2 normal prostate epithelial cells[1]. MS115 (serial dilutions; 5-6 days) TFA degrades PRMT5/MEP50 in normal epithelial cell lines (MCF10A, PNT2) without significant cytotoxicity[1].
References:
[1]. Zhong Y, et al. Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader. J Med Chem. 2025;68(8):8543-8563.
In Vivo, MS115 (TFA) (50 mg/kg; i.p.; single dose) exhibits favorable mouse pharmacokinetic properties with rapid absorption and sustained plasma exposure following a single 50 mg/kg intraperitoneal injection[1].
In Vitro, MS115 (2.1 μM; 120 min) TFA inhibits PRMT5 methyltransferase activity in a cell-free assay with an IC50 of 2.1 μM[1]. MS115 (0.01-5 μM; 3-72 h) TFA potently and selectively degrades PRMT5 (DC50: 17.4 nM) and MEP50 (DC50: 11.3 nM) in MDAMB468 cells in concentration- and time-dependent manners, achieving >85% maximum degradation of both proteins[1]. MS115 (0.5-5 μM; 24-72 h, with 1-2 h pretreatment for mechanism assays) TFA mediates PRMT5/MEP50 degradation in MDAMB468 cells that requires binding to both PRMT5 and VHL, and proceeds via the ubiquitin-proteasome system[1]. MS115 (serial dilutions; 7 days) TFA inhibits MDAMB468 cell proliferation with a gIC50 of 5.6 μM[1]. MS115 (serial dilutions; 5 days) TFA inhibits proliferation of MDAMB453, MDAMB231, and MCF7 breast cancer cells, with potency comparable to the PRMT5 inhibitor GSKi[1]. MS115 (0.004-5 μM; 7 h-3 days) TFA potently degrades PRMT5/MEP50 in PC-3 prostate cancer cells, showing greater efficacy than the PRMT5 degrader MS4322[1]. MS115 (0.5-5 μM; 3 days) TFA degrades PRMT5/MEP50 in MCF10A normal breast epithelial cells and PNT2 normal prostate epithelial cells[1]. MS115 (serial dilutions; 5-6 days) TFA degrades PRMT5/MEP50 in normal epithelial cell lines (MCF10A, PNT2) without significant cytotoxicity[1].
References:
[1]. Zhong Y, et al. Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader. J Med Chem. 2025;68(8):8543-8563.