SET domain-containing protein 8 (SETD8) is a methyltransferase that selectively monomethylates histone H4 at lysine residue 20 (H4K20), an event proven to have an important role in chromatin structure and transcriptional activation. It is also a regulator of p53, mono-methylating lysine 382 of the tumor suppressor. Ryuvidine is an inhibitor of SETD8 (IC50 = 0.5 μM) that suppresses monomethylation of H4K20 in vitro. It less potently inhibits cyclin-dependent kinase 4 (Cdk4; IC50 = 6 μM for Cdk4/cyclin D1). Over several hours of treatment, ryuvidine suppresses the expression of cell division cycle 7-related kinase (Cdc7), resulting in an ATM-dependent checkpoint response and arrest of cell cycling in S phase.
