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Issue 2, 2015
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Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites

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Abstract

The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors may therefore hold potential as a means of developing new therapeutics. We here report the synthesis and evaluation of a series of small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity were observed when testing these compounds against a panel of methyltransferases.

Graphical abstract: Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites

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Publication details

The article was received on 13 Aug 2014, accepted on 23 Oct 2014 and first published on 23 Oct 2014


Article type: Paper
DOI: 10.1039/C4OB01734J
Citation: Org. Biomol. Chem., 2015,13, 549-560
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    Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites

    M. van Haren, L. Q. van Ufford, E. E. Moret and N. I. Martin, Org. Biomol. Chem., 2015, 13, 549
    DOI: 10.1039/C4OB01734J

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