With the advent of the “RNA Revolution,” the exponential elucidation of RNA roles in various diseases has led to it being noted as an attractive therapeutic target. The progress of RNA-binding small molecules to target and modulate RNA structures as therapeutic leads has been met with roadblocks due to a lack of guiding principles for RNA:small molecule binding. Recent work from our laboratory has demonstrated that quantitative structure activity relationship (QSAR) models can be used to connect the molecular descriptors of a given small molecule with its binding and activity on a specific RNA target. One of these RNA targets includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which has been implicated in several human diseases, including cancer. MALAT1 is overexpressed in several cancers, and knockdown of this transcript leads to a reduction in tumor size and a restoration of a healthy phenotype. Structurally, MALAT1 possesses a triple helix structure that serves as a stability element, protecting the transcript from exonucleolytic degradation and promoting its accumulation. Therefore, creating small molecules that can regulate MALAT1 through this triple helix could lead to identification of novel drug candidates.<br/> Our lab and others have previously reported small molecules that bind to the MALAT1 triple helix and affect its stability. Recently, through the screening of a focused synthetic library based on the diminazene scaffold, we identified molecules with the ability to stabilize and destabilize the triple helix. Through this data, we trained preliminary QSAR models for binding affinity, enzymatic degradation, and thermal stabilization, linking these measures to the small molecules’ properties. Herein, we report results on expanding these QSAR models to synthetically enrich the diminazene library for the purpose of creating improved binders and modulators for the MALAT1 triple helix.

Expansion of existing diminazene scaffold library and QSAR model for modulation of MALAT1 triple helix

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