The mammalian protein arginine methyltransferases are a group of nine enzymes that perform NG-mono methylation-, asymmetric-, or symmetric dimethylation of arginine residues on a range of nuclear and cytoplasmic protein substrates. Protein arginine methyltransferase-5 (PRMT5) is one member of this group which catalyzes the transfer of up to two methyl groups to arginine residues, forming ω-NG-monomethyl arginine and symmetrical ω-NG-dimethyl arginine on protein substrates[3]. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity with IC50 of 22 nM[4]. SCID mice bearing subcutaneous mantle cell lymphoma cell lines Z-138 and Maver-1 xenografts were orally given EPZ015666 on four doses: 25, 50, 100 and 200 mg/kg twice daily. Dosing at 200 mg/kg induced tumor stasis in Z-138 cells, with >93% tumor-growth inhibition (TGI) after 21 d, whereas Maver-1 cells showed >70% TGI[4]. EPZ0156660 (0 to 10 uM) dose-dependently inhibited the proliferation of multiple myeloma cell lines[5]. EPZ015666 at 5 uM also inhibited growth in patient multiple myeloma (pMM) cells cultured on a BMSCs monolayer, and also induced apoptosis of pMM cells within bone marrow mononuclear cell cultures[5]. 10 uM -EPZ treatment significantly suppressed the proliferation of several human glioblastoma cell lines: GI261, T98G, U-87 MG and A172, with loss of active S phase cells and accumulation of G2/M populations, but did not induce apoptosis[6].
作用机制
EPZ015666 binds in the peptide-binding site of PRMT5, including in the pocket occupied by the substrate arginine side chain.
EPZ015666 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CD138+ pMM cells
5 µM
6 days
EPZ015666 significantly inhibited the growth of CD138+ pMM cells
Leukemia. 2018 Apr;32(4):996-1002.
H929 cells
0 to 10 µM
EPZ015666 significantly inhibited the proliferation of H929 cells in a dose-dependent manner
Leukemia. 2018 Apr;32(4):996-1002.
KMS11 cells
0 to 10 µM
EPZ015666 significantly inhibited the proliferation of KMS11 cells in a dose-dependent manner
Leukemia. 2018 Apr;32(4):996-1002.
EPZ015666 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD SCID mice
GFP+-KMS11 xenograft model
Oral
150 mg/kg
Twice daily for 21 days
EPZ015666 significantly inhibited tumor growth and prolonged survival in mice
Leukemia. 2018 Apr;32(4):996-1002.
C57BL/6j mice
Pressure overload-induced heart failure model
Oral
30 mg/kg/day
Once daily for 8 weeks
EPZ015666 significantly improved pressure overload-induced cardiac fibrosis and dysfunction, and suppressed cardiac hypertrophy and fibrosis-related gene expression.
Nat Commun. 2024 Mar 19;15(1):2472
C57BL/6J mice
Carotid artery ligation model
Oral
50 mg/kg
Twice daily for 3 weeks
EPZ015666 markedly attenuated neointimal formation induced by carotid artery ligation in mice.
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