In drug discovery, “undruggable targets” refer to biological molecules, often proteins, that play a role in disease but have historically been difficult or impossible to influence with conventional drug approaches. While traditional drugs work by binding to specific sites on these molecules, many disease-related targets lack such accessible features, making them unresponsive to current therapies. Despite these challenges, these targets are increasingly becoming a focus for innovative research.
Understanding Undruggable Targets
Many biological targets are considered “undruggable” due to their structural characteristics and cellular roles. A common issue is the absence of a suitable binding pocket, a specific indentation on a protein where a drug molecule can attach. Unlike enzymes with well-defined active sites, many undruggable proteins, such as transcription factors, lack these pockets, making it challenging for small molecules to bind.
Some proteins exhibit a highly dynamic or “intrinsically disordered” nature, meaning they do not maintain a stable, fixed three-dimensional structure. Instead, they adopt multiple conformations, making it difficult for a drug to consistently interact with them and form a durable binding site.
The location of a target within the cell can present a barrier. While extracellular targets are often more accessible to larger drug molecules like antibodies, intracellular targets, especially those within the nucleus or other organelles, require small molecules that can readily cross cell membranes.
Another challenge arises when a protein is involved in many essential cellular pathways. Broadly inhibiting such a protein could lead to widespread, undesirable side effects. For instance, some proteins function by interacting with others, forming large, diffuse interaction surfaces rather than small, well-defined pockets, which are difficult for traditional small molecules to disrupt specifically.
Innovative Strategies to Target the Undruggable
Overcoming the challenges of undruggable targets has led to several innovative strategies beyond traditional small molecule inhibition. One approach is Targeted Protein Degradation (TPD), involving molecules like Proteolysis-Targeting Chimeras (PROTACs) and molecular glues. Instead of merely blocking a protein’s function, PROTACs act as a bridge, bringing the target protein close to the cell’s natural waste disposal system, the proteasome, leading to its complete elimination.
Allosteric modulation offers another way to influence protein function without directly targeting the active site. These molecules bind to a different, “allosteric” site on the protein, causing a conformational change that indirectly affects its activity. This method is useful for targets that lack a traditional binding pocket, as it leverages other parts of the protein’s structure.
RNA-targeting therapies represent a distinct approach by interfering with the genetic instructions that lead to protein production. These therapies, such as antisense oligonucleotides or small interfering RNAs (siRNAs), can prevent messenger RNA (mRNA) from being translated into a disease-causing protein or alter gene expression. This bypasses the need to directly interact with the problematic protein.
Computational approaches, including artificial intelligence (AI) and machine learning, are accelerating the discovery process for difficult targets. These methods can analyze vast amounts of data to predict potential binding sites, design novel molecules, and simulate their interactions with proteins, speeding up the identification of new drug candidates. This allows researchers to explore a broader chemical space than traditional screening methods.
Gene editing technologies, such as CRISPR-Cas9, offer the potential to address undruggable targets at their source: the genetic level. By precisely modifying DNA, these technologies can correct disease-causing mutations or alter gene expression, preventing the production of problematic proteins. Gene editing opens new avenues for treating diseases driven by difficult targets.
Transforming Disease Treatment
The advancements in targeting previously undruggable molecules are transforming disease treatment, offering hope for conditions that currently lack effective therapies. Many cancers, for example, are driven by proteins like KRAS and MYC, long considered impossible to drug. KRAS, a protein mutated in approximately 30% of human cancers, was a challenging target due to its shallow and polar binding pockets.
Recent breakthroughs have led to the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, which have shown clinical success in specific lung and colorectal cancers. These drugs work by irreversibly binding to a mutant form of KRAS, trapping it in an inactive state and preventing it from promoting cell growth. This represents a significant step forward in treating difficult KRAS-driven tumors.
Beyond cancer, targeting the undruggable holds promise for neurodegenerative disorders, where many disease-related proteins are difficult to access or lack clear binding sites. Autoimmune conditions, often involving complex protein-protein interactions, could also benefit from therapies that precisely modulate or degrade specific immune-related proteins. As research continues to uncover new mechanisms and develop more sophisticated tools, the potential for new therapies for a wide range of diseases continues to grow.