From Undruggable To Druggable: The Science Reshaping Small Molecule Discovery
By Ping Cao, Ph.D., BridGene Biosciences
For decades, drug developers have wrestled with the reality that most biologically validated disease-relevant protein targets remain chemically inaccessible. These so-called “undruggable” targets, which make up an estimated 90 percent of the human proteome, have long resisted conventional small molecule approaches. But that narrative is beginning to shift. A new wave of scientific innovation is steadily expanding the scope of drug discovery, paving the way for a future where many elusive disease drivers can be therapeutically addressed.
Traditional small molecule discovery methods have had great success with certain types of proteins — those that possess well-defined binding pockets or enzymatic active sites where small molecules can bind with high affinity. But many important disease targets are shaped differently. They might lack obvious binding pockets, consist of intrinsically disordered regions, or exist within complex intracellular protein-protein interactions that are difficult to modulate.
For example, transcription factors such as c-Myc represent a particularly challenging target class. c-Myc plays a central role in cancer cell proliferation, but it is largely intrinsically disordered and lacks a defined ligand-binding pocket, making it notoriously undruggable by traditional small molecules.
Such properties make these targets difficult to drug using structure-guided or ligand-based design strategies. Consequently, countless therapeutic opportunities, especially in oncology, neurodegenerative diseases, and autoimmune disorders, have remained out of reach.
A New Generation Of Tools And Approaches
But the definition of “druggable” is rapidly evolving, thanks to powerful new technologies. One example is live-cell chemoproteomics, which enables the screening of small molecules against the entire proteome within a physiologically relevant, live-cell context. Rather than relying solely on predicted binding pockets, this method captures real-time interactions as they occur inside cells, revealing novel opportunities for therapeutic intervention.
Covalent bonding is another emerging strategy. By forming a stable, often irreversible bond with the target protein, covalent small molecules can access shallow or transient binding sites that would otherwise evade conventional compounds. A notable example is sotorasib (AMG 510), the first approved covalent inhibitor targeting the KRAS G12C mutation — a target long considered undruggable due to its lack of deep binding pockets.
In parallel, molecular glues and PROTACs (proteolysis-targeting chimeras) are redefining drug modality itself. Rather than inhibiting protein function, these compounds exploit the cell’s natural protein degradation machinery. By recruiting disease-relevant proteins to E3 ubiquitin ligases, they promote selective degradation, offering a novel mechanism to eliminate hard-to-target proteins such as transcription factors or scaffolding proteins.
Additionally, advances in AI and machine learning, exemplified by tools like AlphaFold, are revolutionizing our understanding of protein structure. These technologies dramatically enhance the ability to model previously uncharacterized or flexible proteins, enabling the rational design of ligands and accelerating the identification of new druggable sites across the proteome.
Together, these innovations are converging to reshape the landscape of drug discovery, turning long-standing challenges into actionable opportunities.
Increasingly Druggable Targets
These scientific breakthroughs are already yielding tangible results. Innovative platforms are integrating multiple approaches, such as covalent chemistry, live-cell screening, and targeted protein degradation to expand the frontiers of drug discovery.
At BridGene, we combine live-cell chemoproteomics, target deconvolution, and mass spectrometry-based screening to discover and validate covalent binders in a physiologically relevant context. This enables the detection of novel binding sites across the proteome — including shallow, transient, or previously unknown pockets — making our approach ideally suited for uncovering starting points against proteins like transcription factors, scaffolding proteins, and other non-enzymatic targets that have long been beyond the reach of traditional approaches.
A compelling example of progress in this space is STAT3, a transcription factor long considered undruggable due to its disordered structure, lack of binding pockets, and nuclear localization. With the advent of targeted protein degradation, this barrier is being overcome. KT-333, a STAT3-targeting PROTAC, has shown selective and sustained STAT3 degradation in vivo, leading to tumor regression in preclinical leukemia models — a major step forward in drugging a once-inaccessible cancer driver.
This evolution marks a critical shift in perspective: rather than viewing certain targets as permanently out of reach, the field is beginning to embrace a more dynamic view of “hard-to-drug” shaped by progress in chemical biology, screening methodologies, and target validation tools.
Broader Implications For Drug Development
This redefinition of druggable holds significant implications for the future of medicine. Expanding the boundaries of what can be targeted could unlock entirely new classes of medicines capable of addressing previously unapproachable disease drivers. In oncology, it may allow drug developers to target intracellular pathways critical to tumor growth or metastasis. In neurology and immunology, it could help modulate key signaling cascades that have long been recognized but never successfully addressed.
This transformation represents a fundamental expansion of the therapeutic landscape from traditional targets like enzymes and receptors to more complex structures such as transcription factors, scaffolding proteins, and intrinsically disordered domains. For patients, this could mean access to truly novel therapies for diseases that have resisted decades of conventional drug discovery, offering real hope where few or no treatment options currently exist.
These approaches also align closely with the broader movement toward precision medicine, where treatments are tailored not just to disease types but to the underlying molecular drivers within each patient. As a result, small molecule therapies are poised to play a more prominent role in the personalized treatment landscape.
For many years, undruggable was treated as a hard line in drug development. But today, it is increasingly seen as a surmountable challenge — one that can be addressed through scientific ingenuity, advanced technologies, and novel chemical approaches. As researchers continue to innovate and explore new chemical spaces, the frontier of hard-to-drug will keep moving, offering new hope for tackling some of the most complex and intractable diseases.
The future of small molecule discovery is not just about finding new drugs — it’s about transforming the very definition of what is possible in the treatment of human diseases.
About The Author:
Ping Cao, Ph.D., is the cofounder and CEO of BridGene Biosciences. With over 20 years of experience in biopharmaceutical research and development, Cao has held key scientific and leadership roles at companies such as Amgen and Tularik. He earned his Ph.D. in analytical chemistry from the University of Texas at Austin and completed a postdoctoral fellowship at Genentech. At BridGene, Cao leads the development of innovative chemoproteomic platforms aimed at targeting previously undruggable proteins to address unmet medical needs in oncology, neurology, and immunology.