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J Med Chem. 2014 Aug 14;57(15):6822-33. doi: 10.1021/jm500871s. Epub 2014 Jul 25.

Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8.

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Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, ‡Department of Pharmacology, School of Medicine, §Lineberger Comprehensive Cancer Center, and ∥Department of Biochemistry and Biophysics, UNC Macromolecular Interactions Facility, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.


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-activity relationships (SAR) of this series.

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