Design, synthesis and biological evaluation of pyrrole derivatives as coactivator associated arginine methyltransferase 1 (CARM1) inhibitors

Coactivator-Associated Arginine Methyltransferase 1 (CARM1, also known as PRMT4) is involved in many biological activities, such as mRNA splicing, cell cycle progression, and DNA damage response. CARM1 levels have shown to be elevated in castration-resistant prostate cancer and aggressive breast tumors. Therefore, selective CARM1 modulators would be valuable chemical tools for investigating the biological functions of the target as well as potential drug candidates for disease treatments. To date only few CARM1 specific modulators have been identified and reported. Among them the pyrazole-based and indole-based compounds exhibit the most potent PRMT4 inhibition, although they lack activity in cell-based assays. For this reason we decided to design and synthesize a new class of CARM1 pyrrole inhibitors (Figure 1), starting from the information obtained from structure-activity relationships of pyrazolic and indolic modulators. Potent inhibition was observed when testing pyrrolic compounds against CARM1 (i.e. EML 438, IC50 = 2.42 μM), nevertheless, they didn’t show a significant cellular activity, due to their poor transcellular permeability. Future developments are the synthesis of new pyrrolic compounds, in order to enhance enzymatic inhibition and cell permeability.