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Issue 12, 2014
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Structure–activity relationship studies of SETD8 inhibitors

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SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure–activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends.

Graphical abstract: Structure–activity relationship studies of SETD8 inhibitors

  • This article is part of the themed collection: Epigenetics
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The article was received on 21 Jul 2014, accepted on 16 Sep 2014 and first published on 17 Sep 2014

Article type: Concise Article
DOI: 10.1039/C4MD00317A
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Med. Chem. Commun., 2014,5, 1892-1898

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    Structure–activity relationship studies of SETD8 inhibitors

    A. Ma, W. Yu, Y. Xiong, K. V. Butler, P. J. Brown and J. Jin, Med. Chem. Commun., 2014, 5, 1892
    DOI: 10.1039/C4MD00317A

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