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Issue 12, 2018
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Probing the hras-1Y i-motif with small molecules

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Non-B DNA structures represent intriguing and challenging targets for small molecules. For example, the promoter of the HRAS oncogene contains multiple G-quadruplex and i-motif structures, atypical globular folds that serve as molecular switches for gene expression. Of the two, i-motif structures are far less studied. Here, we report the first example of small organic compounds that directly interact with the hras-1Y i-motif. We use a small molecule microarray screen to identify drug-like small molecules that bind to the hras-1Y i-motif but not to several other DNA or RNA secondary structures. Two different lead compounds, 1 and 2, were discovered to have 7.4 ± 5.3 μM and 5.9 ± 3.7 μM binding affinity by surface plasmon resonance and similar affinity by fluorescence titration. A structure–activity relationship (SAR) was developed and two improved analogues of 2 demonstrated submicromolar binding affinities. Both compounds display pH-dependent binding, indicating that they interact with the DNA only when the i-motif is properly folded. Chemical shift perturbation shows that 1 alters the structure of the i-motif, while 2 has no effect on the i-motif conformation, indicating different modes of interaction.

Graphical abstract: Probing the hras-1Y i-motif with small molecules

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The article was received on 25 Jun 2018, accepted on 19 Sep 2018 and first published on 05 Oct 2018

Article type: Research Article
DOI: 10.1039/C8MD00311D
Citation: Med. Chem. Commun., 2018,9, 2000-2007

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    Probing the hras-1Y i-motif with small molecules

    S. N. Journey, S. L. Alden, W. M. Hewitt, M. L. Peach, M. C. Nicklaus and J. S. Schneekloth Jr, Med. Chem. Commun., 2018, 9, 2000
    DOI: 10.1039/C8MD00311D

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