University of Florida Research Foundation, Incorporated (20240293398). Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor... simplified abstract

Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor...

Organization Name

University of Florida Research Foundation, Incorporated

Inventor(s)

Matthew D. Disney of Jupiter FL (US)

Sai Pradeep Velagapudi of Jupiter FL (US)

Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor... - A simplified explanation of the abstract

This abstract first appeared for US patent application 20240293398 titled 'Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor...

The patent application introduces a method called High Throughput Structure-Activity Relationships through Sequencing (HIT-STARTS) to evaluate the affinity and selectivity of RNA motif-small molecule interactions identified through selection processes.

• HIT-STARTS is a statistical approach that compares input nucleic acid sequences to selected library members that bind a ligand via high throughput sequencing.
• The method allows for the definition of the fitness landscape of hundreds of thousands of RNA motif-small molecule binding partners.
• The application of this method led to the identification of an interaction between a small molecule and the Dicer nuclease-processing site in the oncogenic microRNA-18a hairpin precursor, a member of the miR-17-92 cluster.
• The small molecule, named Targapremir-18a, was found to inhibit the production of miR-18a, de-repress serine/threonine protein kinase 4 protein (STK4), and trigger apoptosis in prostate cancer cells.
• Chemical cross-linking and isolation by pull-down (Chem-CLIP) studies confirmed the specific binding of Targapremir-18a to the miR-18a precursor, revealing factors that govern small molecule drugging of non-coding RNAs.

Potential Applications: - Targeted therapy for cancer by inhibiting specific microRNAs. - Development of small molecule drugs that target non-coding RNAs.

Problems Solved: - Lack of methods to design small molecules targeting RNA motifs. - Limited understanding of the interactions between small molecules and non-coding RNAs.

Benefits: - Facilitates the development of precision medicine approaches for cancer treatment. - Provides insights into the druggability of non-coding RNAs.

Commercial Applications: Title: Targeted Cancer Therapy Using Small Molecule Inhibitors of Non-Coding RNAs Potential commercial uses include pharmaceutical companies developing novel cancer therapies and biotechnology firms focusing on RNA-targeted drug discovery.

Questions about RNA Drug Targets: 1. How does the HIT-STARTS method compare to traditional methods of evaluating RNA motif-small molecule interactions? 2. What are the implications of targeting specific microRNAs like miR-18a in cancer therapy?

Original Abstract Submitted

rna drug targets are pervasive in cells but methods to design small molecules that target them are sparse. herein, we report a general approach to score the affinity and selectivity of rna motif-small molecule interactions identified via selection. named high throughput structure-activity relationships through sequencing (hit-starts), hit-starts is statistical in nature and compares input nucleic acid sequences to selected library members that bind a ligand via high throughput sequencing. the approach allowed facile definition of the fitness landscape of hundreds of thousands of rna motif-small molecule binding partners. these results were mined against folded rnas in the human transcriptome and identified an avid interaction between a small molecule and the dicer nuclease-processing site in the oncogenic microrna (mir)-18a hairpin precursor, which is a member of the mir-17-92 cluster. application of the small molecule, targapremir-18a, to prostate cancer cells inhibited production of mir-18a from the cluster, de-repressed serine/threonine protein kinase 4 protein (stk4), and triggered apoptosis. profiling the cellular targets of targapremir-18a via chemical cross linking and isolation by pull down (chem-clip), a covalent small molecule-rna cellular profiling approach, and other studies showed specific binding of the compound to the mir-18a precursor, revealing broadly applicable factors that govern small molecule drugging of non-coding rnas.