SET　and　MYND　domain-containing　protein　2　(SMYD2),　a　lysine　methyltransferase,　is　reported　to　catalyze　the　methylation　of　lysine　residues　on　histone　and　non-histone　proteins.　As　a　potential　target　for　cancer　therapy,　there　are　several　SMYD2　inhibitors　are　reported,　LLY-507　as　a　cell-active　inhibitor　exhibits　submicromolar　potency　against　SMYD2　in　several　cancer　cell　lines.　To　know　which　structural　fragment　of　LLY-507　is　suitable　for　chemical　modification,　three　sites　are　chosen　for　structure-activity　relationship　studies　(SARs).　Among　our　focused　library,　compounds　43　and　44　with　amide　link　on　site　C　showed　reasonably　improved　potency　indicating　that　modification　on　this　fragment　is　more　flexible　and　introduction　of　electrophilic　warheads　in　this　position　might　provide　lysine-targeting　covalent　inhibitors　for　SMYD2.