Discovery of Isoxazone Amides as Potent and Selective SMYD3 Inhibitors

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, co-crystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis, biological and pharmacokinetic profiles of compounds are also presented.