From “Undruggable” to Precision Targeting: How the RAS Target Was Finally Conquered

By:DengYue International Business Division

For decades, RAS has been regarded as one of the most important yet most challenging driver genes in cancer biology. Since its discovery in the 1980s, RAS mutations have been identified across a wide range of solid tumors, including pancreatic cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. However, due to the lack of exploitable drug-binding sites, its extremely high affinity for GTP, and its complex signaling mechanisms, RAS remained a classic example of an “undruggable target” for nearly forty years.

The approval of the KRAS G12C inhibitor Sotorasib in 2021 fundamentally changed this perception. This milestone was followed by the development of Adagrasib, Divarasib, Olomorasib, and a new generation of pan-RAS inhibitors, transforming RAS from a longstanding research challenge into one of the most important frontiers in global oncology drug development.

The success of RAS-targeted therapies has delivered new treatment options for patients with cancer. More importantly, it has reshaped the industry's understanding of what constitutes an "undruggable" target. Proteins once considered impossible to drug are now being redefined through advances in structural biology, chemical biology, targeted protein degradation technologies, and artificial intelligence-assisted drug design.

Rethinking “Undruggable”: Where Did the Challenge Really Lie?

In public discourse, the term “undruggable” is often interpreted as meaning that a drug simply cannot be developed against a target.

In reality, a more accurate definition is:

Existing drug discovery technologies are unable to effectively identify and exploit druggable binding sites on a target protein.

Traditional small-molecule drug discovery is built upon a fundamental assumption: the target protein contains a sufficiently deep and stable binding pocket that allows a drug molecule to enter and modulate its function.

This paradigm has been highly successful for many classical therapeutic targets.

For example, kinase proteins such as EGFR, ALK, BRAF, and BTK possess well-defined ATP-binding sites, making them naturally suitable for small-molecule drug development.

RAS, however, is fundamentally different.

Its surface is remarkably smooth and lacks obvious cavities, preventing researchers from identifying a suitable structural space for drug binding over many years.

More importantly, even if a molecule could bind to RAS, such binding would not necessarily inhibit its biological function.

This distinction represents one of the most fundamental differences between RAS and conventional oncology drug targets.

Why Did RAS Become the “King of Undruggable Targets”?

Among all so-called undruggable targets, RAS presents a uniquely formidable challenge.

First, RAS proteins lack natural druggable pockets. For more than two decades, researchers analyzed numerous RAS structures using X-ray crystallography but consistently failed to identify a small-molecule binding region capable of accommodating a therapeutic compound.

Second, RAS binds GTP with exceptionally high affinity. Functionally, RAS acts as a molecular switch within the cell. It is active when bound to GTP and inactive when bound to GDP.

In theory, the most straightforward therapeutic strategy would be to develop compounds that compete with GTP for binding.

The challenge, however, lies in the extraordinary affinity between RAS and GTP, which reaches the picomolar range. Furthermore, intracellular GTP concentrations are substantially higher than the concentrations achievable by most therapeutic agents.

In other words, even if a competitive inhibitor could be designed, it would struggle to exert meaningful activity under physiological conditions.

The third challenge arises from the biology of RAS itself.

RAS is not a tumor-specific protein. Normal cells also rely on RAS signaling to regulate growth, survival, and metabolism.

Consequently, any inhibitory strategy lacking mutation selectivity carries the risk of causing significant toxicity.

Together, these factors explain why RAS drug development remained stalled for nearly four decades.

The Turning Point: How Structural Biology Changed the Rules of the Game

The true breakthrough in RAS drug discovery did not originate from medicinal chemistry alone—it emerged from advances in structural biology.

Early studies generally treated proteins as static structures.

However, during the 21st century, scientists increasingly recognized that proteins exist in a state of continuous motion.

Proteins are not fixed sculptures; they are dynamic systems that constantly fluctuate between different conformations.

With the advancement of nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics simulations, and high-resolution crystallography, researchers began to uncover previously hidden conformational states of RAS.

In 2013, the laboratory of Kevan Shokat discovered that the KRAS G12C mutant transiently exposes a previously unrecognized cryptic pocket when bound to GDP.

This structural feature was later named the Switch-II Pocket (S-IIP).

From a drug discovery perspective, this finding was revolutionary.

It demonstrated that RAS did not lack a binding pocket altogether.

Rather, the pocket was concealed within specific dynamic conformations of the protein.

The reason for decades of failure was not that RAS was inherently undruggable, but that available technologies were unable to visualize the relevant structural state.

This realization represents perhaps the most significant conceptual shift in the history of RAS research.

Why Was G12C the First KRAS Mutation to Be Successfully Targeted?

From an epidemiological perspective, KRAS G12C is not the most common KRAS mutation.

Both G12D and G12V occur more frequently in cancer patients.

Nevertheless, G12C possesses a unique advantage.

At codon 12, glycine is replaced by cysteine.

For medicinal chemists, cysteine serves as an ideal chemical anchor.

Small molecules can form covalent bonds with the cysteine residue, creating highly stable interactions.

This means researchers no longer need to compete directly with GTP.

Instead, they can exploit the cysteine residue to anchor a drug near the Switch-II Pocket, thereby locking KRAS into its inactive state.

This strategy effectively bypasses the central obstacle that had frustrated the field for decades.

Both Sotorasib and Adagrasib were developed based on this principle.

Their success does not stem from traditional competitive inhibition but rather from a novel combination of structure-guided targeting and covalent chemistry.

From G12C to G12D: The Second Technological Revolution Has Begun

If G12C demonstrated that RAS can be drugged, G12D will determine whether RAS-targeted therapies can address the broader patient population.

KRAS G12D accounts for approximately 45% of KRAS mutations in pancreatic cancer and is also highly prevalent in colorectal cancer.

Unlike G12C, however, G12D lacks a cysteine residue.

As a result, the covalent targeting strategies that defined the G12C era cannot be directly applied.

This challenge has forced the industry to develop entirely new approaches.

Three emerging technological strategies have attracted particular attention in recent years.

The first involves highly selective non-covalent inhibitors.

The second focuses on RAS(ON) inhibitors, which target the active, GTP-bound state of RAS.

The third involves tri-complex strategies, which exploit interactions among multiple molecular components to achieve target engagement.

What these approaches share is a departure from simply occupying a pre-existing pocket.

Instead, they leverage the dynamic conformational behavior of proteins to create new modes of molecular interaction.

Fundamentally, the logic of drug discovery has evolved from finding pockets to creating pockets.

What Has RAS Really Changed?

The significance of RAS extends far beyond a single oncology target.

In many ways, it has fundamentally altered how the pharmaceutical industry defines the boundaries of drug discovery.

Over the past two decades, drug developers have generally prioritized proteins with clearly defined binding sites because they offer lower development risk.

The success of RAS has demonstrated that:

● Protein structures are not fixed.

● Binding sites do not necessarily have to exist naturally.

● Drug molecules themselves can participate in creating new binding interfaces.

This paradigm shift has accelerated the development of multiple emerging fields, including:

● PROTAC-based targeted protein degradation

● Molecular glues

● Covalent drug design

● AI-assisted drug discovery

● Dynamic conformational drug design

In many respects, RAS stands as one of the defining achievements of the modern chemical biology era.

Which “Undruggable Target” Will Be Conquered Next?

Following the success of RAS, industry attention has increasingly shifted toward even more challenging cancer drivers.

Among the most closely watched are:

● MYC

● p53

● β-catenin

● YAP/TAZ

These proteins face many of the same obstacles that once defined RAS, including the absence of obvious binding pockets, complex protein-protein interactions, and highly dynamic conformational behavior.

Yet the success of RAS has already demonstrated an important principle:

Undruggability is not a biological fact—it is often a reflection of technological limitations at a given point in time.

As cryo-electron microscopy (Cryo-EM), artificial intelligence, targeted protein degradation platforms, and advanced chemical biology tools continue to mature, an increasing number of previously inaccessible targets are re-entering the drug discovery landscape.

Over the next decade, the most important question in drug development may no longer be:

“Is this target druggable?”

But rather:

“Do we possess the technologies necessary to make it druggable?”

At the same time, patients are increasingly focused on practical questions that extend beyond the laboratory:

● Should I undergo comprehensive NGS testing?

● Am I eligible for a clinical trial?

● Are innovative therapies already available overseas?

● When will these new treatments become accessible locally?

These questions are no longer confined to academic research; they have become common topics in real-world patient consultations.

As an organization dedicated to monitoring advances in oncology innovation and cross-border healthcare services, DengYue has observed a steady increase in inquiries related to KRAS-targeted therapies in recent years, particularly among patients with lung cancer, pancreatic cancer, and colorectal cancer.

Conclusion

The four-decade journey of RAS drug development represents one of the most remarkable stories in the history of modern drug discovery.

Beyond providing new therapeutic options for patients with lung cancer, pancreatic cancer, and colorectal cancer, the success of RAS has fundamentally expanded the industry's understanding of what is possible in drug development.

From a target believed to have no druggable pockets to one with exploitable cryptic binding sites; from failed attempts to compete with GTP to successful covalent targeting of mutant residues; from static structural analysis to dynamic conformational drug design—the RAS story is, at its core, a story of technological innovation.

Today, as the industry confronts the next generation of challenging targets such as MYC and p53, the greatest legacy of RAS may not be any single approved therapy.

Rather, it is a new conviction:

A target is not undruggable because it cannot be drugged. It is undruggable only until the right technology is found.

As DengYue Medicine continues to follow developments in RAS-targeted therapies, cell and gene therapies, rare disease medicines, and other breakthrough innovations, we remain committed to sharing meaningful scientific advances and clinically relevant developments from across the global healthcare landscape.