How decades of advances in structural biology, protein science, drug discovery, and assay development transformed one of oncology's most challenging targets.

The recent FDA approval of RASONQUE™ (daraxonrasib), a RAS inhibitor targeting the most common form of pancreatic cancer, marks a milestone for both patients and researchers working in one of the most challenging areas of cancer research. What was once considered an "undruggable" target has now become the foundation for a growing class of precision therapies.

The approval of daraxonrasib is a meaningful moment for the KRAS field. But, as with most scientific breakthroughs, this moment didn't arrive as the result of a single discovery. Rather, it reflects decades of progress across structural biology, protein science, medicinal chemistry, drug screening, assay development, and translational research. We spoke with scientists across Cayman Chemical's expert teams to explore how the field arrived at this moment, what it means for researchers, and where the science is headed next.

Why "Undruggable" Doesn't Mean Impossible

For years, KRAS was considered one of the most difficult targets in drug discovery.

"From a protein science perspective, KRAS lacks many of the obvious structural features drug developers traditionally rely on when designing small molecule inhibitors," explains Dr. Zahra Assar-Nossoni, Director of Protein Sciences and Structural Biology at Cayman Chemical.

As researchers learned more about the structure and behavior of KRAS, however, new opportunities began to emerge. According to Assar-Nossoni, high-resolution structural biology played a critical role in changing how scientists viewed the target.

"Structural biology has been essential to progress in the KRAS field because it helped transform KRAS from a historically 'undruggable' target into one with FDA-approved targeted therapies," Assar-Nossoni points out. "High-resolution structures reveal druggable pockets, define inhibitor-binding modes, guide improvements in potency and selectivity, and help researchers understand mechanisms of resistance."

"By combining high-resolution structural biology with the development of high-quality KRAS proteins, our teams help provide both the molecular insights and research tools needed to advance the next generation of KRAS-targeted therapies," she highlights.

This work extends beyond the development of inhibitors themselves. Members of Cayman's Protein Sciences and Structural Biology teams have contributed both high-quality recombinant KRAS proteins and high-resolution KRAS crystal structures, helping researchers better understand the molecular architecture of the target and how potential therapies interact with it.

And as the KRAS field continues to evolve, these foundational tools remain critical for researchers who look to understand (and expand upon) current therapeutic approaches. Understanding a target, however, is only the beginning. Even after researchers identify a promising biological mechanism, the path to a viable therapy remains long and uncertain.

"Candidate targets for cancer drug development are often selected based on their importance in growth or signaling pathways associated with cancer development and progression," explains Dr. Marie Foss, Scientist II, Cellular Metabolism & High-Throughput Screening at Cayman Chemical.

Once a target is identified, researchers can move to screening strategies in order to find the compounds capable of modulating its activity. High-throughput screening can allow scientists to evaluate hundreds of thousands, or even millions, of compounds to find the most promising candidates and then begin optimizing them through medicinal chemistry. But success is far from guaranteed.

"There are numerous ways compounds may fail during development," Foss says. "A target may behave differently in whole animals than it does in tissue culture. Compounds may show excellent activity but lack the drug-like properties necessary to become effective therapeutics."

For decades, researchers worked to develop new technologies and to challenge existing assumptions about what was possible. And this persistence paid off, ultimately opening the door to entirely new classes of molecules, including approaches that go beyond traditional enzyme inhibition.

Foss points out that the KRAS story also reflects a broader shift in drug discovery, where new approaches are allowing researchers to pursue a wider range of targets in innovative ways.

"Today, there are many additional ways to approach small-molecule drug development. For targets like KRAS, molecular glues and modulators of protein structure can significantly impact interactions with binding partners and their downstream functions," Foss notes. "Developing libraries and tools for macrocycle drug development enables pursuit of this drug class, which can successfully break some traditional drug development guidelines. This is especially important for molecular glues, which benefit from greater surface-area coverage on a target."

The Future of Oncology Isn't One Drug

Many oncology-focused drug development programs have, historically, searched for a single "magic bullet" approach to cancer treatment. Increasingly, researchers are recognizing that cancer's ability to adapt often requires more sophisticated treatment strategies.

Cancer cells are remarkably adaptable, Foss points out, and even highly effective therapies can eventually encounter resistance, which is why researchers are increasingly focusing on combination approaches. Rather than viewing targeted therapies, immunotherapies, personalized cancer vaccines, ADCs, and cell therapies as competing modalities, they're increasingly considered complementary tools that may ultimately be used together.

This trend is particularly visible in the growing interest around personalized cancer vaccines, including recent clinical progress reported by Merck and Moderna in melanoma. As the field gains a deeper understanding of the molecular drivers behind individual tumors, therapies directed at targets such as KRAS may increasingly be explored alongside immune-based approaches that are designed to help the body recognize and attack cancer more effectively.

And as therapies become more sophisticated, so do the tools used to evaluate them. According to Daniel Tew, Director of ELISA and Assay R&D at Cayman Chemical, assay development and biomarker research play an essential role in translating scientific discoveries into viable therapeutic strategies.

"Identification and validation of new assays and biomarkers help elucidate unknown mechanisms and biological pathways," Tew says. "These findings support, validate, and drive therapeutic development."

Researchers increasingly rely on reporter assays, transcription factor assays, metabolic assays, biomarker profiling, and cell-based screening systems to understand not only whether a therapy works, but why it works. These tools become especially important as research investigates more complex biological interactions involving both cancer cells and the immune system. And understanding those interactions may prove critical for future advances in precision oncology.

Understanding the interaction between targeted therapies and the immune system is becoming increasingly important as scientists seek to improve responses in difficult-to-treat cancers. Tumors are often described as being either "hot" or "cold." Hot tumors tend to contain substantial immune cell infiltration (which makes them more likely to respond favorably to immunotherapies), whereas cold tumors often evade immune recognition, making them more difficult to treat. Many cancers driven by KRAS mutations have historically displayed features associated with immunologically cold tumors, making the approval of daraxonrasib especially notable for patients and researchers. New reports already show that daraxonrasib could prove effective against a variety of tumors, including promising early results against lung cancer.

The natural question becomes what's next? Because this approval is not the end of the KRAS story. In many ways, it marks the beginning of a new phase of drug development. Researchers are already exploring next-generation KRAS and Ras targets, resistance mechanisms, immunotherapy combinations, antibody-drug conjugates (ADCs), tumor microenvironment modulation, and personalized cancer vaccines.

For Foss, the future is particularly exciting around advances in immunotherapy. "Harnessing the immune system to clear cancer cells has the potential to provide treatments that are less toxic and more durable than traditional chemotherapeutics," she points out.

For Tew, antibody-based therapeutics and ADCs remain among the most promising areas of oncology. And for Assar-Nossoni, the continued integration of structural biology, protein science, and translational research will help unlock the next generation of previously inaccessible drug targets.

As KRAS and oncology research continues to evolve, the scientific community requires more than just therapeutic candidates. Researchers also need the tools that make discovery possible.

The approval of daraxonrasib represents an important milestone, but researchers widely view it as the beginning of a new chapter rather than the end of the story. Questions surrounding resistance mechanisms, combination therapies, tumor microenvironment modulation, and immune engagement will likely drive the next wave of innovation. Recent research has already begun shedding light on how the field may evolve. In a 2026 study of acquired resistance to daraxonrasib, investigators identified multiple mechanisms by which tumors can restore RAS pathway signaling and highlighted several promising combination therapy strategies, underscoring both the progress made and the need for continued innovation in KRAS-directed therapies. If the past decade has demonstrated that KRAS is druggable, the next may reveal how targeted therapies can be combined with other modalities to deliver even greater benefits for patients.

Cayman Chemical is proud to support researchers across the KRAS discovery workflow with our industry-leading research tools (including recombinant KRAS proteins and KRAS-targeted small molecules and inhibitors) and scientific capabilities like biomarker development and activity screening, structural biology expertise, biophysical characterization, assay development, and structure-based drug design support.

As Cell Therapy Evolves, the Technology is Maturing

The journey of KRAS from "undruggable" target to approved therapy highlights the power of scientific innovation, and how advances in structural science and drug discovery can unlock previously inaccessible therapeutic targets. Our recent article, As Cell Therapy Evolves, the Technology is Maturing, explores a complementary challenge facing the industry today, around how to translate promising scientific breakthroughs into scalable and reproducible therapies capable of reaching more patients.