Protein lysine methyltransferases are important regulators of epigenetic 
signaling. These enzymes catalyze the transfer of donor methyl groups from 
S-adenosylmethionine to specific acceptor lysines on histones, leading to 
changes in chromatin structure and transcriptional regulation. These enzymes 
also methylate nonhistone protein substrates, revealing an additional mechanism 
to regulate cellular physiology. The oncogenic protein SMYD2 represses the 
functional activities of the tumor suppressor proteins p53 and Rb, making it an 
attractive drug target. Here we report the discovery of AZ505, a potent and 
selective inhibitor of SMYD2 that was identified from a high throughput chemical 
screen. We also present the crystal structures of SMYD2 with p53 substrate and 
product peptides, and notably, in complex with AZ505. This substrate competitive 
inhibitor is bound in the peptide binding groove of SMYD2. These results have 
implications for the development of SMYD2 inhibitors, and indicate the potential 
for developing novel therapies targeting this target class.