LLY-507 (LLY507) is a novel, potent, cell-permeable/active and selective inhibitor of protein-lysine methyltransferase SMYD2 (SET And MYND Domain Containing 2) with potential anticancer activity. It inhibits SMYD2 with an IC50 of 15 nM. SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. LLY-507 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.