A novel arginine methyltransferase inhibitor with cellular activity

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Cancer Research

Background:

• Protein arginine methyltransferases (PRMTs) play crucial roles in cellular processes.
• Dysregulation of PRMTs is implicated in the development of various cancers, including hormone-dependent types.
• Targeting PRMTs offers a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To identify novel inhibitors of fungal (RmtA) and human (PRMT1) protein arginine methyltransferases.
• To evaluate the potential of identified compounds as therapeutic agents for hormone-dependent cancers.

Main Methods:

• Virtual screening was employed to identify potential PRMT inhibitors.
• In vitro assays were used to test the inhibitory activity of compounds against RmtA and PRMT1.
• Cell-based assays (HepG2 cells) were performed to assess the biological effects of the lead compound.
• Molecular docking studies were conducted to predict the binding mode of the inhibitor.

Main Results:

• A thioglycolic amide derivative was identified as a potent inhibitor of PRMTs.
• Compound RM65 demonstrated the highest potency and druglike properties, with an IC(50) of 55.4 microM against PRMT1.
• RM65 induced histone hypomethylation in HepG2 cells, indicating PRMT inhibition in a cellular context.
• Docking studies suggested that the inhibitor binds to the substrate and SAM cofactor binding pocket of PRMTs.

Conclusions:

• The identified thioglycolic amide derivative, particularly compound RM65, represents a promising lead for the development of novel PRMT inhibitors.
• These PRMT inhibitors may hold therapeutic potential for the treatment of hormone-dependent cancers.
• Further optimization of this chemical scaffold could lead to more potent and selective PRMT-targeted cancer therapies.