SETD8 is a histone methyltransferase that catalyzes the monomethylation of histone H4K20. Overexpressed in cancer, several studies have suggested that it could be a potential target for treatment in certain tumors. However, there are currently very few SETD8 inhibitors, and all of them have bad pharmacological properties. Based on previously published structures of SETD8 bound to an H4K20me peptide, we have discovered a new chemical series of SETD8 inhibitors. As part of the characterization of these molecules, we conducted Thermal Proteome Profiling, aiming to discover potential additional targets as well as a better understanding of the signaling pathways that are affected by the drug.