Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8
Anqi Ma 1, Wenyu Yu, Fengling Li, Rachel M Bleich, J Martin Herold, Kyle V Butler, Jacqueline L Norris, Victoria Korboukh, Ashutosh Tripathy, William P Janzen, Cheryl H Arrowsmith, Stephen V Frye, Masoud Vedadi, Peter J Brown, Jian Jin

The lysine methyltransferase SETD8 may be the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 continues to be implicated in controlling diverse biological processes such as the DNA damage response. Additionally to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only real known selective inhibitor of SETD8 up to now is nahuoic acidity A, a marine natural product, that is as good as the cofactor. Here, we report the invention from the first substrate-competitive inhibitor of SETD8, UNC0379 (1). This small-molecule inhibitor is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, compound 1 is selective for SETD8 over 15 other methyltransferases. We describe structure-activity relationships (SAR) of the series.