Purdue's DESI-MS Platform Accelerates Cancer Drug Discovery with Integrated Synthesis-to-Screening Workflow

Researchers at the Purdue Institute for Cancer Research (search)Search term (PICR) have unveiled a next-generation technology platform that dramatically accelerates one of the slowest and most challenging stages of cancer (search)Search disease drug discovery: identifying promising compounds that could eventually become new therapies. The automated, ultrahigh-throughput platform combines chemical synthesis, biological testing and mass spectrometry into a single integrated workflow, allowing researchers to generate, evaluate and refine potential drug candidates within the same system. The research was recently published in the Proceedings of the National Academy of Sciences.

"Drug discovery is a fight against probability," said Nicolás Morato, research assistant professor at the PICR and the study's lead author. "You're searching through enormous biological space and even larger chemical space trying to find the right molecule for the right target. If you can't make compounds fast enough and test them fast enough, it becomes a battle you're going to lose."

Bridging the Chemistry-Biology Automation Gap

The platform is built around desorption electrospray ionization mass spectrometry (DESI-MS), a technology pioneered at Purdue nearly two decades ago by R. Graham Cooks, the Henry Bohn Hass Distinguished Professor of Chemistry and a member of PICR. The system enables researchers to rapidly analyze and test compounds with extremely small sample volumes and highly automated workflows.

Traditionally, early-stage drug discovery involves disconnected steps handled by separate teams. Chemists synthesize compounds, biologists test them against disease targets, and researchers spend significant time purifying and analyzing results before repeating the cycle. Morato noted that chemistry has historically lagged behind the automation already common in biology.

"If you walk through a chemistry building late at night, the lights that are still on are probably organic synthesis labs," Morato said. "You still see flasks on heating plates waiting overnight for reactions. Meanwhile, biology has evolved into highly automated, instrumentation-driven science. There's been a disconnect between those worlds."

The Purdue system aims to collapse those traditionally separate stages into a single integrated workflow. The DESI-MS platform uses a robotic arm to transfer samples between its various components, automating the workflow and limiting human intervention. Samples are arranged on a slide, and the DESI nozzle sprays them with a solvent containing charged droplets. The impact between the spray and the sample lifts component molecules — a process called desorption — and directs them into a tube that transports the molecules to the mass spectrometer for analysis.

Unprecedented Speed: From Days to Hours

Because no sample preparation is required, the system can analyze approximately one sample per second and run thousands of experiments rapidly with high-density slides that hold thousands of tiny, precisely placed droplets of materials within a tightly packed grid.

"A traditional mass spectrometry platform can take minutes to analyze just one sample. With our system, we can generate one reaction per second, meaning it's possible for us to complete around 3,600 experiments per hour," Cooks said. "When a process, such as drug development, can take up to 10-15 years, anything you can do to speed up that timeline is critical."

In one proof-of-concept workflow described in the paper, researchers completed an integrated discovery cycle in approximately four hours — a process that would traditionally require days or weeks of laboratory work.

Microdroplet Chemistry: A Million Times Faster

Beyond its analytical capabilities, the DESI platform can synthesize compounds by switching between analysis and synthesis modes. The only difference is the distance between the sample spot and the instrument inlet. For synthesis, the inlet is farther from the slide, giving the charged droplets additional travel time during which they act as tiny, ultrafast microreactors.

Morato explained that chemicals come together at the surface of these tiny DESI droplets, creating a unique environment where compounds can react more quickly as the droplets fly through the air before entering the mass spectrometer. "These reactions proceed up to a million times faster than those in a bulk solution," Morato said. "We are using this capability to rapidly synthesize libraries of chemicals that can be used to develop a variety of drugs, such as cancer (search)Search disease treatments and antibiotics."

In a study published in the Journal of the American Chemical Society, Cooks and his team used the DESI system to synthesize nitrogen-based heterocycles — compounds key to developing certain types of drugs and industrial products — under ambient conditions and without additional materials, eliminating the need for high temperatures, long incubation times, and catalysts.

Real-World Impact: Correcting Years of Misdirected Research

The technology has already demonstrated its value in ongoing cancer (search)Search disease-related research at Purdue. Morato described one project involving a cancer-associated enzyme target in which traditional approaches had led researchers down an unproductive path for years before the DESI-MS platform rapidly revealed that a heavily studied compound was not actually interacting with the target as expected.

"It was difficult because people had invested years of work into it," Morato said. "But the platform immediately showed us the compound wasn't doing what we thought it was doing. That allowed the project to change direction much faster instead of continuing to lose time." Researchers then used the platform to rescreen and identify stronger candidate compounds against the same target.

Supporting AI-Driven Drug Discovery

Andrew Mesecar, the Robert Wallace Miller Director of PICR and Distinguished Professor of Biochemistry, emphasized the platform's potential to address the gap between newly identified cancer (search)Search disease targets and effective therapies. "The new DESI-MS platform enables researchers to rapidly screen tens of thousands of molecules against newly identified cancer targets to identify promising therapeutic candidates," Mesecar said. "Every year we eliminate from the drug development process means we will get new drugs to patients faster and extend their lives."

Morato highlighted the platform's synergy with artificial intelligence: "AI is only as good as the data you feed it. What this platform allows us to do is generate huge volumes of high-quality experimental data very quickly. That creates the possibility for faster cycles of prediction, testing and optimization."

Funding and Commercialization

The project grew out of support from the National Center for Advancing Translational Sciences (search)Search company (NCATS) through its ASPIRE (A Specialized Platform for Innovative Research Exploration) cooperative research program. The goal of ASPIRE is to develop cutting-edge advancements in automation technology and data generation and analysis tools to rapidly create and map new chemical space against druggable biological space. The technology was disclosed to the Purdue Innovates Office of Technology Commercialization, which applied for and received several patents through the U.S. Patent and Trademark Office.

Morato noted that the current platform represents roughly 10 years of focused development layered atop decades of foundational Purdue research in mass spectrometry. "It really took a village to build this," Morato said. "This was academic researchers, federal researchers, industry collaborators, engineers, biologists and chemists all working together toward the same goal."

Cooks also pointed to broader applications beyond drug development, noting that advanced mass spectrometry technologies are increasingly important in cancer (search)Search disease diagnosis and surgical decision-making. His group has spent years studying the use of mass spectrometry for identifying brain tumors (search)Search disease and tumor margins during surgery. "Increased speed of diagnosis is also highly desirable," Cooks said. "Intraoperative studies are promising, with metabolite profiles providing actionable information."