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Aimed at developing potent inhibitors of SETD7 that can also act as small molecule substrates, we replaced the pyrrolidine ring of (<jats:italic>R<\/jats:italic>)\u2010PFI\u20102 with several side chains bearing nucleophilic functional groups. We explored the inhibitory activity of 20 novel (<jats:italic>R<\/jats:italic>)\u2010PFI\u20102 analogues, and found that the most potent analogue has a hydroxyethyl side chain (<jats:bold>7<\/jats:bold>). SETD7\u2019s ability to catalyse methylation of (<jats:italic>R<\/jats:italic>)\u2010PFI\u20102\u2010based small molecules was evaluated by mass spectrometric assays, and we observed efficient methylation of analogues bearing lysine mimicking nucleophilic amines. The optimal side chain was found to be an aminoethyl group (<jats:bold>1<\/jats:bold>), which was surprisingly also dimethylated by SETD7. The work demonstrates that small molecules can act as both substrates and inhibitors of biomedically important SETD7.<\/jats:p>","DOI":"10.1002\/cmdc.202300457","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T22:59:11Z","timestamp":1698101951000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["(<i>R<\/i>)\u2010PFI\u20102 Analogues as Substrates and Inhibitors of Histone Lysine Methyltransferase SETD7"],"prefix":"10.1002","volume":"18","author":[{"given":"Miriam R. 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