Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8

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• 作者：Anqi Ma ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6822-6833
• 全文大小：442K
• ISSN：1520-4804

文摘

The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition 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 known selective inhibitor of SETD8 to date is nahuoic acid A, a marine natural product, which is competitive with the cofactor. Here, we report the discovery of 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 also describe structure鈥揳ctivity relationships (SAR) of this series.