IP Library › Granted Patent US 12,527,788
Granted Patent B2
US 12,527,788 · App. 16/486,223 · Granted Jan 20, 2026

Defining RNA-small molecule affinity landscapes enables design of a small molecule inhibitor of an oncogenic non-coding RNA

Inventors: Matthew D. Disney (Jupiter, FL); Sai Pradeep Velagapudi (Jupiter, FL)
Assignee: University of Florida Research Foundation, Incorporated
A61K31/496A61P35/00C07D235/18C12N15/1065
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Quick Facts
Patent No.
US 12,527,788
App. No.
16/486,223
Granted
Jan 20, 2026
Kind
B2
Abstract

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.

Claims (23)

1 . A compound of the formula:

2 . The compound of claim 1 , wherein the compound is of the formula:

3 . The compound of claim 1 , wherein the compound is of the formula:

4 . The compound of claim 1 , wherein the compound is of the formula:

5 . The compound of claim 1 , wherein the compound is of the formula:

6 . A method of inhibiting production of microRNA (miR)-18a, in a prostate cancer cell, from the oncogenic miR-18a hairpin precursor of the miR-17-92 cluster, comprising contacting the prostate cancer cell with an effective amount of a compound of the formula:

7 . The method of claim 6 , wherein the compound of the formula:

contacting the prostate cancer cell further de-represses serine/threonine protein kinase 4 protein and triggers apoptosis of the prostate cancer cell.

8 . The method of claim 6 , wherein the compound of the formula:

contacting the prostate cancer cell further de-represses serine/threonine protein kinase 4 protein and triggers apoptosis of the prostate cancer cell.

9 . The method of claim 6 , wherein the compound of the formula:

contacting the prostate cancer cell further de-represses serine/threonine protein kinase 4 protein and triggers apoptosis of the prostate cancer cell.

10 . The method of claim 6 , wherein the compound of the formula:

contacting the prostate cancer cell further de-represses serine/threonine protein kinase 4 protein and triggers apoptosis of the prostate cancer cell.

11 . The method of claim 6 , wherein the compound is of the formula:

12 . The method of claim 6 , wherein the compound is of the formula:

13 . The method of claim 6 , wherein the compound is of the formula:

14 . The method of claim 6 , wherein the compound is of the formula:

15 . A method of treatment of prostate cancer, comprising administering to a mammal afflicted therewith an effective dose of a compound of the formula:

16 . The method of claim 15 , wherein the compound is of the formula:

17 . The method of claim 15 , wherein the compound is of the formula:

18 . The method of claim 15 , wherein the compound is of the formula:

19 . The method of claim 15 , wherein the compound is of the formula:

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 15, 2022
From: THE SCRIPPS RESEARCH INSTITUTE
To: UNIVERSITY OF FLORIDA BOARD OF TRUSTEES
Reel/Frame 061177/0338 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 15, 2022
From: UNIVERSITY OF FLORIDA BOARD OF TRUSTEES
To: UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED
Reel/Frame 061177/0491 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2021
From: DISNEY, MATTHEW D.; VELAGAPUDI, SAI PRADEEP
To: THE SCRIPPS RESEARCH INSTITUTE
Reel/Frame 056621/0141 →
Continuity (2)
Provisional Application 62460184 · Feb 17, 2017
Related Publication 20240293398A1 · Sep 5, 2024
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