MS023 is an inhibitor of type I protein arginine methyltransferases (PRMTs; IC50s = 30, 119, 83, 4, and 5 nM for PRMT1, -3, -4, -6, and -8, respectively). It is selective for these type I PRMTs over PRMT5, -7, and -9, as well as a panel of 25 protein lysine methyltransferases (PKMTs) and DNA methyltransferases (DNMTs) when used at a concentration of 10 μM. It inhibits the methylation of histone 4 at arginine 3 (H4R3) in MCF-7 breast cancer cells (IC50 = 9 nM) and H3R2 in HEK293 cells (IC50 = 56 nM). MS023 (20 μM) also inhibits the methylation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein and the replication of SARS-CoV-2 in Vero E6 cells. It reduces tumor growth in a Huh7 mouse xenograft model when administered at a dose of 160 mg/kg.
MS023 trihydrochloride is a potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases (PRMTs) inhibitor, with IC50s of 30, 119, 83, 4 and 5 nM for PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8, respectively[1].
ms023 was identified to have high potency for type i prmts including prmt1, -3, -4, -6, and -8 but was inactive against type ii and type iii prmts, protein lysine methyltransferases as well as dna methyltransferases. the crystal structure of prmt6 with ms023 indicated that ms023 bound to the substrate binding site. moreover, ms023 could potently decrease the cellular levels of histone arginine asymmetric dimethylation. in cells, ms023 also ould reduce the levels of arginine asymmetric dimethylation and increase levels of arginine monomethylation and symmetric dimethylation. therefore, ms023 is a useful chemical tool for testing the role of type i prmts in health and disease [1].
Administration of MS023 (160 mg/kg, i.p) in combination with PKC412 (100 mg/kg, i.g.) blocks MLL-r acute lymphoblastic leukemia (ALL) propagation by inhibiting maintenance of functional MLL-r ALL-initiating cells[2].
| Animal Model: | NOD-scid IL2Rgnull (NSG) mice bearing primary MLL-r ALL cells[2] |
| Dosage: | 160 mg/kg |
| Administration: | Intraperitoneal injection; PKC412 (100 mg/kg, i.g.), MS023 (160 mg/kg, i.p), or a combination for 4 weeks |
| Result: | Combinatorial treatment extended survival of leukemic mice relative to single treatments. |
20, 119, 83, 8, and 8 nm for prmt1, 3, 4, 6, and 8, respectively
[1] m. s. eram, y. shen, m. m. szewczyk, et al. a potent, selective, and cell-active inhibitor of human type i protein arginine methyltransferases. acs chemical biology 11.8.15, (2015).
