The field of drug discovery is constantly evolving, but there is a significant challenge in this progression: The "undruggables".
The field of drug discovery is constantly evolving. Pursuing novel therapeutic targets is essential to further advance medicine. "Undruggables" are a large group of potential drug targets that are currently therapeutically inaccessible and make up over 90% of the human proteome [Equation](1–3). The traditional druggable targets are extensively explored, leading to saturation in the market and a need for innovative strategies. In this blog, we explore the methods that are used to target these clinically meaningful molecules and discuss the challenges of "undruggables".
Innovative strategies to target "undruggables"
In recent years there has been a surge in efforts to improve the druggability of these targets by developing innovative strategies and technologies.
- Multi-specific drugs: These therapeutics interact with multiple targets simultaneously. This approach enhances specificity and efficacy and reduces off-target effects and toxicity. These drugs have shown promise in treating complex diseases with precision.
- PROTACs: Proteolysis-targeting chimeras (PROTACs) utilize the ubiquitin-proteasome degradation pathway, and can target a broader range of molecules.
- Oligonucleotide therapeutics: This class of therapeutics targets genetic elements, offering a strategy to modulate gene expression.
- PPI modulators: PPI modulators disrupt or enhance specific protein interactions that are crucial in diseases like cancer and are gaining traction as a viable strategy for targeting complex protein networks.
Remaining challenges and future direction
Significant challenges remain with these innovative strategies. Their structural complexity, and achieving specificity and selectivity is an obstacle that must be overcome before these approaches are clinically beneficial. Ongoing research and development has led to several therapeutics targeting "undruggables" to reach the market or clinical trials. The current boundaries of druggable targets are likely to expand, leading to more precise therapeutic strategies.
If you are interested in staying ahead of the latest trends in revolutionizing drug discovery, take a look at our latest whitepaper. We dig deeper into innovative strategies aiming to target "undruggables" and explore other emerging trends in the field.
References
- Stockwell BR. The Quest for the Cure: The Science and Stories behind the next Generation of Medicines. Columbia University Press; 2013.
- Santos R, Ursu O, Gaulton A, et al. A comprehensive map of molecular drug targets. Nature Reviews Drug Discovery. 2016;16(1):19-34. doi:10.1038/nrd.2016.230.
- Bologa C, Holmes J, Mani S, et al. Unexplored opportunities in the druggable human genome. Macmillon Publishers Limited. Published online 2016. Accessed November 23, 2023. https://media.nature.com/full/nature-cms/uploads/ckeditor/attachments/8200/nrd_druggablegenome.pdf.