Over the past decade researchers at the Purdue Institute of Cancer Research have been working to better automate the process of identifying promising compounds that could assist with cancer drug recovery.
Recently, a next-generation technology platform was developed by researchers at Purdue University’s Purdue Institute for Cancer Research (or PICR). The technology aims to greatly speed up the process of identifying promising drugs that could someday become new therapies, which is currently one of the most difficult, and slowest, parts of cancer drug recovery.
The institute has created an automated and ultrahigh-throughput program that combines mass spectrometry, biological testing, and chemical synthesis, into a single unified process. This allows researchers to create and test new potential drug treatments all simultaneously. The research was recently published in the Proceeding of the National Academy of Science journal. The work that went into the paper was conducted for over a decade at Purdue. Researchers hope that their work will help the medical community be able to more quickly act against certain difficult to treat cancers.
In an article published on Purdue University’s website, research assistant professor at the PICR and the study’s lead author, Nicolás Morato, talked about the importance of his team’s work, saying, “Drug discovery is a fight against probability. 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.”
The new platform is designed around a process called desorption electrospray ionization mass spectrometry (or DESI-ME). The technology was created at Purdue and allows researchers the capability to quickly analyze and test various drugs and other compounds without having to have access to large samples.
Up until now, early-stage drug discovery has been undertaken by separate teams through a series of disconnected tests. Chemists need to create new compounds, biologists then test them against various diseases, and then researchers are tasked with analyzing and purifying the results of those tests before the cycle can be repeated.
According to Morato, automation has historically been slower to develop in the field of chemistry than in biology.
“If you walk through a chemistry building late at night, the lights that are still on are probably organic synthesis labs. 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,” he said.
The team at Purdue hopes that their new system will link those normally separate steps into one streamlined workflow to more quickly discover beneficial potential drugs.
According to Andrew Mesecar, who serves as the Robert Wallace Miller Director of the Purdue Institute for Cancer Research, as well as the Walther Professor in Cancer Structural Biology and as a Distinguished Professor of Biochemistry, most of the newly identified cancer targets are being developed thanks to computational research, artificial intelligence, and modern genomics.
“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. Every year we eliminate from the drug development process means we will get new drugs to patients faster and extend their lives,” he said.
So far, this new technology has played a part in some of the ongoing cancer related research taking place at Purdue University. Morato talked about one project that involves a cancer-associated enzyme target that researchers have been stumped on using more traditional methods prior to the development of the DESI-MS platform. Using the new platform, the researchers discovered that one of their most studied compounds was not interacting with the enzyme as they expected.
Morato talked about the bittersweet discovery, saying, “It was difficult because people had invested years of work into it. 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.”
From there the research team went on to use the DESI-MS platform to rescreen candidate compounds to find a stronger candidate against their target enzyme.
Around the same time the research project began to use the new translational drug discovery platform, Morato’s grandfather was diagnosed with prostate cancer, making the work feel more personal. He spoke on this shift, saying, “We weren’t just developing technology for the sake of developing technology anymore. We were building something that could hopefully help move treatments to patients faster.”
The various stages of early drug discovery the new system can perform can be done at speeds that normally take laboratory teams days or weeks of work. Purdue’s team conducted a proof-of-concept workflow, illustrated in the paper linked above, that took only four hours to complete an integrated discovery cycle.
R. Graham Cooks is a chemist at Purdue, and was part of the team that initially invented DESI almost twenty years ago. The new platform is the newest link in a long evolutionary chain of spectrometry technologies, especially as it relates to drug discovery and medicine.
Cooks also serves as a member of the PICR and as the Henry Bohn Hass distinguished Professor of Chemistry in the James Tarpo Jr. and Margaret Tarpo Department of Chemistry at Purdue’s College of Science. He talked about the importance of mass spectrometry, saying, “Mass spectrometry is now a very important part of drug discovery. Every large pharmaceutical company now has hundreds of scientists whose prime instrumentation is a mass spectrometer.”
Cooks noted that one of the biggest obstacles in drug discovery is that it takes a long time: “The Achilles’ heel of drug discovery is its low speed. This platform increases the speed of several distinct aspects of drug discovery.”
Cooks went on to talk about how the new technology makes screening chemical reactions much quicker by automatically analyzing the way products react using online mass spectrometry technology. This makes biological testing able to happen much more quickly through automated processes, and allows for direct-to-biology testing which lets researchers skip the long purification process.
The new mass spectrometry technologies also have other use cases including surgical decision making and cancer diagnosis. Cooks’ team has spent the last few years looking into its use for tumor margins during surgery and identifying brain tumors.
Cooks’ talked about these benefits as well saying, “increased speed of diagnosis is also highly desirable. Intraoperative studies are promising, with metabolite profiles providing actionable information.”
Morato also spoke on the broader aim behind the new platform. Noting that it is not just about faster chemistry, but creating a more streamlined and repeatable approach to various discoveries. He also noted how this will be useful as artificial intelligence tools become more ubiquitous, saying, “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.”
Creating methods that allow for more quickly developed data sets, the new platform could allow for new approaches to drug discovery that are powered by artificial intelligence.
The National Center for Advancing Translational Sciences’ ASPIRE (or A Specialized Platform for Innovative Research Exploration) cooperative research program was instrumental in getting this project off the ground.
ASPIRE’s goal is to create new data generation and analysis tools as well as automation technology advancements in order to more quickly map new chemical discoveries along with the biological processes. The team led by Cooks created a system that is now part of a group of technologies and tools the ASPIRE program uses to work on closing the translational gap in developing preclinical drug creation by making the chemical synthesis to biological testing cycle much quicker.
The new technology was presented to the Purdue Innovates Office of Technology Commercialization, which then went on to apply for and receive several patents from the U.S. Patent and Trademark Office.
Morato also emphasized that the new platform is the result of over a decade of teamwork and development based on decades of mass spectrometry research conducted at Purdue. He said, “It really took a village to build this. This was academic researchers, federal researchers, industry collaborators, engineers, biologists and chemists all working together toward the same goal.”
Morato also talked about how the researchers do not want this platform to stay solely at Purdue, saying, “As tool developers, you want people to actually use what you build. What excites me most now is seeing this technology begin to help researchers working on meaningful disease and discovery challenges.”
This research was conducted as part of Purdue University’s One Health Initiative, which collects research on animal, plant, and human health. The research was conducted through the initiative’s focus on advanced chemistry, using complex chemical systems to create new applications and techniques.
More information about Purdue University can be found at the school’s website.