LLY-507 is a potent, selective and cell permeable protein lysine methyltransferase SMYD2 inhibitor with IC50 <15 nM. It binds in the substrate peptide-binding pocket. It has >100-fold selectivity over other methyltransferases and other non-epigenetic targets. LLY-507 has been shown to inhibit p53K370 monomethylation in cells with an IC50 ~600 nM. It inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.