In drug discovery, a target is described as “undruggable” if it cannot be tackled pharmacologically. These targets can for example be protein-protein interactions without defined binding pockets, transcription factors, or RNAs. In the past, they included many important cancer-driving proteins like the oncogenes RAS and MYC. However, scientists did not take no for an answer and hence much progress has been made towards new drug classes enabling the targeting of formerly “undruggable” molecules.

One well-known example is the RAS family of proteins. The protooncogene RAS is mutated in many cancers, causing continuous stimulation of cell proliferation. It has long been conceived as “undruggable” due to the lack of binding pockets on its surface. In 2022, an allele-specific covalent inhibitor of KRAS was approved as the first treatment for RAS-mutant tumours, constituting another step towards personalized medicine.

Another new therapeutic modality investigated in the context of hard-to-drug targets are proteolysis targeting chimeras (PROTACs). These bifunctional molecules bind the target protein as well as an E3 ligase, bringing them in close proximity to induce the proteasome-mediated degradation of the target. Since they do not require a functional and high affinity target binding site, their target scope is higher than that of classical inhibitors. PROTACs therefore have the potential to target undrugged proteins. To tap into the full potential of targeted protein degradation, more insights into PROTAC biology and mechanisms is needed. For example, the pool of utilized E3 ligases needs to be expanded and the physicochemical properties of PROTACs (e.g. cell permeability) need to be improved.

A further emerging class are RNA-binding small molecules or compounds targeting non-coding RNAs, e.g. riboswitches or aptamers. With only 3% of all RNAs having a protein-coding function, the investigation of non-coding RNAs that have important regulatory functions offers so far hardly explored opportunities for drug discovery. It has been revealed that, contrary to previous assumptions, RNA can adopt specific structures that can potentially be used as binding pockets for small molecules. In 2020, risdiplam was approved as the first drug specifically targeting a messenger RNA. RNA as a target for small molecules is still relatively unexplored and offers new possibilities to increase the druggable proteome.

With the switchSENSE® technology you can identify and optimize new treatment modalities like PROTACs or RNA binders by using one of the following application examples or by setting up your own drug discovery assay.


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