Progress in the Development of Lysine Methyltransferase SETD8 Inhibitors

SETD8/SET8/Pr‐SET7/KMT5A is the only known lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20) in vivo. The methyltransferase activity of SETD8 has been implicated in many essential cellular processes, including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. In addition to H4K20, SETD8 monomethylates non‐histone substrates including proliferating cell nuclear antigen and p53. During the past decade, different structural classes of inhibitors targeting various lysine methyltransferases have been designed and developed. However, the development of SETD8 inhibitors is still in its infancy. This review covers the progress made to date in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases, and cellular activity. Quest for SETD8 inhibitors: Lysine methyltransferase SETD8/SET8/Pr‐SET7/KMT5A plays a key role in the regulation of transcriptional activity and is implicated in many human diseases comprising cancer. However, the development of SETD8 inhibitors is still in its infancy. This review covers the progress made in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases, and cellular activity.