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

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

doi:10.1021/jm500871s

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

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

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	6822-6833
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	15
DOIs	https://doi.org/10.1021/jm500871s
State	Published - 14 Aug 2014
Externally published	Yes

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Ma, A., Yu, W., Li, F., Bleich, R. M., Herold, J. M., Butler, K. V., Norris, J. L., Korboukh, V., Tripathy, A., Janzen, W. P., Arrowsmith, C. H., Frye, S. V., Vedadi, M., Brown, P. J., & Jin, J. (2014). Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. Journal of Medicinal Chemistry, 57(15), 6822-6833. https://doi.org/10.1021/jm500871s

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title = "Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8",

abstract = "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.",

author = "Anqi Ma and Wenyu Yu and Fengling Li and Bleich, {Rachel M.} and Herold, {J. Martin} and Butler, {Kyle V.} and Norris, {Jacqueline L.} and Victoria Korboukh and Ashutosh Tripathy and Janzen, {William P.} and Arrowsmith, {Cheryl H.} and Frye, {Stephen V.} and Masoud Vedadi and Brown, {Peter J.} and Jian Jin",

year = "2014",

month = aug,

day = "14",

doi = "10.1021/jm500871s",

language = "English",

volume = "57",

pages = "6822--6833",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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T1 - Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8

AU - Ma, Anqi

AU - Yu, Wenyu

AU - Li, Fengling

AU - Bleich, Rachel M.

AU - Herold, J. Martin

AU - Butler, Kyle V.

AU - Norris, Jacqueline L.

AU - Korboukh, Victoria

AU - Tripathy, Ashutosh

AU - Janzen, William P.

AU - Arrowsmith, Cheryl H.

AU - Frye, Stephen V.

AU - Vedadi, Masoud

AU - Brown, Peter J.

AU - Jin, Jian

PY - 2014/8/14

Y1 - 2014/8/14

N2 - 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.

AB - 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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U2 - 10.1021/jm500871s

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SP - 6822

EP - 6833

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

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

Abstract

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