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


ABSTRACT: 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 ?M and 5.9 ± 3.7 ?M 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.

SUBMITTER: Journey SN 

PROVIDER: S-EPMC6301200 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Probing the <i>hras</i>-1<sup>Y</sup> i-motif with small molecules.

Journey Sara N SN   Alden Stephanie L SL   Hewitt Will M WM   Peach Megan L ML   Nicklaus Marc C MC   Schneekloth John S JS  

MedChemComm 20181005 12


Non-B DNA structures represent intriguing and challenging targets for small molecules. For example, the promoter of the <i>HRAS</i> 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 <i>hras</i>-1<sup>Y</sup> i-motif. We use a small molecule microarray screen to  ...[more]

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