Long non-coding RNAs (lncRNAs) are functional yet non-protein-coding RNAs that have crucial roles in many oncogenic processes. Characterization of select transcripts has provided insights into intricate tertiary structures that are crucial for their function. For example, the 3’-terminal RNA triple helix in the lncRNA MALAT1 is found to be pivotal in stabilization and nuclear retention of this transcript. As nuclear accumulation of MALAT1 leads to an increase in oncogenic processes in numerous cancers, we propose that disrupting the triple helix will result in ablation of oncogenic activity. To test this hypothesis, we chose to utilize small molecules due to their ability to penetrate cells and affect a specific region of a much larger biomolecule. Towards this goal, we first rationally designed and synthesized a 33-member library of small molecules based on a diphenylfuran scaffold (DPF). In addition, we are developing a first-in-class high-throughput screening platform based on differential scanning fluorimetry (DSF) for quick identification of ligands that bind and destabilize the MALAT1 triple helix<i>.</i> Preliminary screening results indicate that current library members have a range of low- to sub-micromolar affinities to the MALAT1 stem loop and show both stabilizing and destabilizing effects on the MALAT1 triple helix. Immediate future work includes biophysical characterization of these interactions and cell-based studies to test for changes in cancer processes as a result of the triple helix disruption. The development of chemical probes for the MALAT1 triple helix will provide valuable insight into the occurrence and function of this unique structure and its role in several human cancers.

Development of chemical probes and high-throughput screening strategies to target an oncogenic RNA triple helix

254th National Meeting (2017)

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