Protein arginine methyltransferases (PRMTs) is one group of posttranslational modification enzymes which catalyze the arginine methylation process. PRMT5, the main type II PRMT, represents a potential target for cardiovascular diseases. It has been shown to serve as an important epigenetic regulator in endothelial cell (EC) function and angiogenesis. However, a thorough understanding of PRMT5 function is lacking because of limited availability of potent and specific inhibitor. The main focus of this proposal is to construct selective PRMT5 inhibitors and further apply them as chemical probes to explore the biological function of PRMT5 in angiogenesis. Our preliminary studies showed that compound K280 is a potent and selective PRMT5 inhibitor and could inhibit EC growth. However, its further development is haunted by stability issue. Our further studies will be centered on two following aspects: (1) design and synthesize K280 analogues with improved PRMT5 potency and stability; (2) evaluate EC behavior (proliferation, migration and tube formation) in response to representative PRMT5 inhibitors, and use quantitative proteomics and western blot to systematically explore PRMT5 substrates in EC.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2016 → 12/31/2017|