M4*
RNA-Binding Small Molecules with a Rigid Core (R-Score)
Prof. Peng Wu, MPI Molecular Physiology; Mao Jiang, MPI Molecular Physiology, TU Dortmund; Dr Yang Liu, MPI Molecular Physiology, TU Dortmund; Daniel Hoesle, MPI Molecular Physiology, TU Dortmund
Max-Planck-Innovation
Challenge
It is challenging to discover RNA binders, partially due to the inherent dynamic nature of RNAs that are backbones. The challenge has been partially addressed by quite a few diverse methods. Apart from natural products, including aminoglycosides and macrolides, that were reported as early examples of RNA-binding molecules, both scaffold-based design and high-throughput approaches have been applied to identify RNA binders, such as DNA-encoded libraries-based screening, dynamic combinatorial chemistry, and automated ligand detection system. Despite of the presence of different discovery techniques, it remains a daunting task to design RNA binders rationally for a given class of RNA target.
Technology
We propose a new scaffold-based design approach for RNA-binders coined as RNA-binding small molecules with a rigid core decorated with RNA-binding fragments (R-Score). Here we choose to demonstrate the technology by targeting the miRNAs miR-21 and miR-17, both of which are overexpressed in cancers and promoted carcinogenesis, for example in lung and breast cancers. Although different miRNA species share high similarities among the individual secondary structures and the corresponding binding fragments, the combination of fragments binding to two or more secondary structures via a single molecule may yield different binding and biological performance.
Commercial Opportunity
There is a huge unmet need in cancer therapy as only limited effective therapeutic options are currently available against the majority of cancer types. For example, both lung and breast cancers are among the top ten most frequently detected cancer types in both male and female patients, the former has an estimated global market value of ~50 billion USD and the latter of ~40 billion USD (both are projected to have a market value of ~2-3 billion EUR for the European Market). Due to factors including side effects of conventional chemotherapies and frequently developed mutations towards targeted therapies, new cancer targets in the RNA field and new anticancer mechanism of action at the post-transcriptional level could yield the high-sought after new clinical performance.
Development Status
The first-generation of R-Score molecules targeting miR-21 and miR-17 has been successfully demonstrated synthetically and evaluated for their RNA-binding affinities in biophysical methods, tested for their anticancer activities in lung and breast cancer cells, and evaluated for their activities in inducing cellular morphological changes in osteosarcoma cells.
Patent Situation
The first patent describing this technology was published on 25.04.2024 with the International publication number of WO 2024/083886 A1.
Further Reading
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