How New Technologies Are Unlocking Previously “Undruggable” Targets

For decades, drug developers have faced the frustrating reality that most disease-causing proteins simply cannot be targeted with conventional medicines. Traditional small-molecule drugs work by fitting into protein binding pockets, like keys into locks. But with around 85% of the human proteome lacking a lock, vast swathes of biology were effectively rendered undruggable.

Now, that picture is changing rapidly. Advances in omics technologies and structural biology are revealing hidden vulnerabilities in proteins once considered beyond reach. At the same time, entirely new classes of therapeutics, molecular glues, protein degraders, and precision-targeted biologics are rewriting the rules of what can be drugged.

The result is a rapidly expanding universe of therapeutic targets with potential applications ranging from rare genetic disorders to common diseases. However, the challenge is not just finding these targets but understanding how to drug them safely and effectively.

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"Nothing in science is truly impossible,” said Dr. Jon Cherry, a lecturer in biological sciences at the University of Greater Manchester. “The methods we use to approach drug discovery are constantly evolving, and that is leading to novel approaches such as targeted small-molecule drugs, or entirely different strategies like linking drugs to gene-editing technologies," he continued.

"To me, 'undruggable' merely means a drug has yet to be discovered for that target." — Dr. Jon Cherry

"Increasingly, 'undruggable' reflects technological limitations rather than biology," added Dr. Tamara Zwain, lecturer of pharmaceutical science at the University of Lancashire. "As new strategies now enable indirect or non-classical ways of modulating protein function." 

Nobel prize-winning technological tools for target discovery

The explosion in druggable targets owes much to two technological revolutions: AI-driven structure prediction and cryo-electron microscopy (cryo-EM). Together, these tools facilitate visualization of proteins in unprecedented detail, revealing binding sites that were invisible just a few years ago.

Notably, the 2024 Nobel Prize in Chemistry recognized advances in protein structure prediction using AI tools. Vast libraries enable researchers to identify potential drug binding sites computationally before ever stepping into a lab. Even more intriguingly, computational approaches can reveal so-called "cryptic pockets", binding sites that only appear when a protein changes shape, and which traditional methods might struggle with, or never detect.

"Structural prediction allows us to look beyond classical active sites and consider allosteric or transient binding regions. It reduces uncertainty early on and helps prioritize targets more confidently, and it also supports downstream decisions on formulation and delivery by clarifying how structure influences accessibility and stability," explained Zwain.

Cherry added: "Even if the results from these protein predictions are not 100% accurate, it enables drug companies and researchers to pinpoint regions within a protein target and quickly advance their work." 

New ways to drug old problems

Even with better structural insights, some proteins remain stubbornly difficult to target with traditional small molecules. Enter a new generation of therapeutic modalities that sidestep the binding pocket problem entirely.

Chief among these are proteolysis-targeting chimeras (PROTACs) and molecular glues. Rather than directly inhibiting a protein's function, these molecules hijack the cell's waste disposal system to degrade the target protein. PROTACs are bifunctional molecules: One end binds the disease-causing protein, and the other recruits the cell’s waste-disposal machinery. Molecular glues work similarly but are smaller, inducing protein-protein interactions that lead to targeted destruction.

"I often describe molecular glues and protein degraders as a shift in mindset rather than just a new technology," Zwain said. "By inducing selective protein removal, these approaches bypass the need for classical binding pockets.”

“This is particularly exciting in cancer research, where many key drivers lack enzymatic activity, and their emergence has redefined what constitutes a viable drug target." — Dr. Tamara Zwain

"These methods tap into the cell's own protein degradation pathway and use it as a means to get rid of difficult drug targets that may lack the characteristics required to be targeted by traditional drugs," added Cherry. "By bringing an E3 ligase into contact with the target protein, an interaction that would not normally occur, the protein becomes tagged with ubiquitin and signposted for destruction via the cell's waste disposal system."

This approach has proven promising for transcription factors, proteins that control gene expression and have long been considered undruggable. Transcription factors typically lack deep binding pockets and work through large, flat protein-protein interfaces. Degrading them, rather than trying to block their function, offers a workaround.

Beyond protein degradation, researchers are also exploring many other modalities: RNA-targeting therapies, covalent inhibitors that form permanent bonds with their targets, and biologics engineered to penetrate cells.

Historically challenging targets, including sodium channels and tau protein, are now being re-examined as new therapeutic strategies emerge. Sodium channels play a key role in pain signaling, and small-molecule channel inhibitors could provide powerful pain relief without the addiction risks of opioids. Similarly, tau protein has emerged as a target for Alzheimer's disease, as therapies targeting amyloid plaques have shown limited success. 

From target discovery to clinical use

Identifying a druggable target is only the beginning. Translating research into a safe, effective medicine involves navigating a minefield of biological complexity, which can cost billions of dollars and decades of research.

Validation is arguably the first hurdle. A target might look promising in cell culture or animal models, but human biology often tells a different story. Genetic evidence linking a target to disease, ideally from human genome-wide association studies, is recognized as a key validation method, significantly improving the odds of clinical success.

Selectivity presents another challenge. Many proteins belong to large families with similar structures. A drug designed for one target may inadvertently affect its relatives, causing side effects. This is particularly problematic for kinases and other enzymes with conserved active sites. Researchers increasingly rely on structural biology and computational modeling to design molecules with exquisite selectivity.

Cherry noted that translation of novel approaches ultimately rests with both industry and regulators:  "Like any drug taken to market, molecular glues and degraders will need to undergo the same stringent processes to ensure safety, which will ultimately end in clinical trials." He warned, "With any 'undruggable' target, you could be dealing with orphan diseases, and there is surely a temptation to fast-track these drugs. That fast-tracking should be limited to the administrative and bureaucratic stages, not the science."

"Promising targets often fail due to poor pharmacokinetics, limited selectivity, or unexpected toxicity," Zwain added. "For complex cancer targets, barriers such as tumor penetration, protein stability, and systemic clearance further complicate development. Discovery biology must be integrated early with formulation science and delivery design to avoid failure later on."

Tissue-specific protein expression adds another layer of complexity—a protein might be essential in one organ but dispensable in another. Drugs that cannot distinguish between these contexts risk toxicity. Strategies such as tissue-selective delivery, prodrugs that activate only in specific environments, and biologics with inherent tissue tropism are all being explored.

Finally, there is the question of patient selection. Some emerging targets are relevant only to small, genetically defined populations. Others may have broader applicability but require biomarkers to identify responders. Balancing the commercial viability of niche therapeutics with the scientific imperative to help patients remains a persistent tension. 

From undruggable to druggable

The druggable universe is expanding, but not all targets are created equal. Some will prove more tractable than others, and attrition rates in drug development remain high. Even with advanced tools, moving from a validated target to an approved medicine typically takes over a decade and costs billions.

Economic considerations loom large. Developing therapies for ultra-rare diseases or targets relevant only to small subsets of common conditions challenges traditional pharmaceutical business models. While academic labs and biotech startups are increasingly filling this gap, sustainable funding mechanisms remain elusive.

Both Cherry and Zwain viewed the next decade as significant.

"I would like to see molecular glues and degraders applied to dementias and neurodegenerative disorders," said Cherry. "Many of these diseases are linked to the accumulation of dysfunctional proteins, so targeting misfolded variants and upregulating them for degradation could be a novel approach. The blood-brain barrier remains a significant challenge, but the small-molecule nature of molecular glues could potentially circumnavigate that."

Zwain added: "This progress will be driven by advances in structural prediction, protein degradation technologies, and targeted delivery systems.

“Progress in delivery science and nanomedicine will be central to making these targets clinically accessible."— Dr. Tamara Zwain.

Still, the trajectory is clear. Technologies that seemed futuristic a decade ago, including AI-predicted structures, targeted protein degradation, and RNA medicines, are now part of mainstream toolkits. The next frontier likely involves even more sophisticated modalities: cell therapies engineered to produce therapeutic proteins on demand, DNA-based medicines, and perhaps interventions we cannot yet imagine.

The historically undruggable proteome is becoming druggable, one target at a time. For patients with diseases long considered untreatable, that shift cannot come fast enough.