The Center for RNA medicine From genome to medicine

Target: Undruggable Diseases

Thousands of known disease targets still have no treatments, due to structural and other difficulties of modifying the targets with medicines. These so-called “undruggable diseases” have included Alzheimer’s, Parkinson’s, types of cancer, types of muscular dystrophy, ALS, heart disease, certain viral diseases, inherited diseases and much more.

We have shown both in vitro and in vivo that for many disease targets, “undruggable” is a misnomer.

Another Route to Treating the Cause of Disease

Most disease targets deemed “undruggable” exist on proteins or DNA, often folded in such a way that their targets are inaccessible to drug molecules. One way to circumvent such challenges lies in modifying the RNA genome, a largely unexplored, target-rich universe. Discovering specific RNA-binding compounds, and then developing complementary strategies to degrade disease-causing RNA, is our specialty.

Our Focus

Until recently, some in the scientific community viewed RNA as an unlikely drug target due to its composition of four nucleotides: adenine, uracil, cytosine and guanine. However, our recent studies have shown that RNA molecules possess both conserved, structured regions and unstructured regions. Thus, thousands of RNA folds provide suitable small-molecule binding targets. Indeed, our team found that multiple long-established, efficacious drugs, possess RNA-binding activity. Drug classes including kinase and topoisomerase inhibitors, for example, have been shown to bind RNA. 

Inforna: A Tool for Structure-Based Drug Design

To expedite the discovery of RNA binding small molecules, we have created a pipeline which mines RNA structural motifs against a database of known RNA motif-small molecule binding interactions, to rapidly identify novel small molecule/RNA interactions in a target of interest.

Key features of the pipeline include:

• Ability to determine RNA structure from primary sequence
• 1,331 RNA structural motifs* (As of May 10, 2023)
• 244 unique small molecules
• 1,936 known small molecule/RNA interactions
• Free and easy to use

RNA Libraries, Artificial Intelligence and Chemoinformatics

RNA structures from experimental and computational approaches can be used for structure-based design and optimization of small molecule binders.

These structures can also be used for 3D-shapesimilarity searches covering screening libraries with millions to billions of entry small molecules. Inforna database provides a unique opportunity for different cheminformatics and AI-based approaches including:

• 2D similarity search exploiting the chemical information encoded in Inforna in the form of different molecular fingerprints.
• 3D shape complementarity of molecular conformers.
• Deep learning-based molecular property prediction to enrich small molecules targeting RNA.
• Combined molecular docking-machine learning for hit expansion using NMR structures.
• Molecular generation applying molecular fingerprint-based variational autoencoder generating diverse drug-like small molecules targeting the RNA.
• Geometric deep-learning models to improve docking procedure and accuracy.

ChemCLIP: A Tool to Pull Down RNA Targets

ChemCLIP (Chemical Cross-Linking Isolated by Pull-down) is an approach to identify the RNA targets of small molecules and metabolites in cells.

It enables validation of targets and empowers more potent ways to manipulate and study their biological function.

In ChemCLIP, small molecules are appended with a reactive module and biotin. When added to cells, the small molecule reacts with its cellular targets and forms a strong, covalent bond. The combination is then isolated and purified. Read more.

Absorb Array and Compound Libraries

We have developed multiple compound libraries of small molecules that favorably bind RNA motifs.

These include Absorb Array, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format.

RiboTAC: Editing RNA to Treat Disease

Ribonuclease targeting chimeras (RiboTAC) link drug-like molecules to linkers that attract the cell’s own recycling enzymes to remove disease-causing segments of RNA.

RNA binding small molecules can be converted into degraders such as Ribonuclease Targeting Chimeras (RiboTAC) by appending them with a recruiter module that locally activates RNase to cleave target RNA via induced proximity.  Compared to the RNA binders, the RiboTAC degraders have the following features:

• Biologically inactive RNA binders can be programmed into potent RiboTAC degraders. Many interactions between RNA targets and small molecules are biologically silent, that is, they do not affect the biological functions.  By converting RNA binders into degraders, however, we can modulate RNA functions in a precise and predictable manner with targeted degradation of the target RNA.
• Target RNA structures can be leveraged to program selective RiboTAC degraders. The endogenous substrate preferences of the recruited RNase can be leveraged to rationally design and optimize the RiboTAC.
• RiboTAC approach can be applied broadly to a wide range of RNA targets. Our published studies have demonstrated the generalizability of the RiboTAC approach by applying it in multiple disease models, ranging from inflammations to cancers and to viral infections.

Links

Disney Lab

Publications

Licensing our Technology

News Releases

News

Coverage in The Scientist: A Quest to Drug RNA

C&EN: The RNA Drug Hunters

C&EN: Small-molecule selectively destroys cancer-associated RNA

UF Health: First ‘Institute Professor’ of The Wertheim UF Scripps Institute inventing new ways to target incurable diseases via RNA

Scitechdaily.com: Breaking COVID-19’s ‘Clutch’ to stop its spread

Licensees and Partners

Expansion Therapeutics

BMS

Lectures and Talks

Podcast

Back of the Napkin: Inspiring Stories from Biotech Pioneers. Matt Disney: Drugging RNA – Pioneering a New Field in Drug Discovery

Contacts