PTPN22 belongs to a broad family of protein tyrosine phosphatases, enzymes that remove phosphate groups from proteins. These phosphate groups act as molecular switches, controlling the activity, location and interactions of signaling proteins. In immune cells, reversible phosphorylation is essential for transmitting signals from receptors that recognize antigens, pathogens or tissue damage. PTPN22 functions as a negative regulator in several of these pathways, helping prevent immune activation from becoming excessive. That protective role is important for maintaining tolerance to the body’s own tissues, but it can also dampen immune responses that might otherwise recognize and attack cancer cells. Genetic studies have linked PTPN22 variants to susceptibility to multiple autoimmune disorders, while experimental deletion of the gene has been associated with stronger antitumor immunity. These observations led Zhang’s group to investigate whether carefully designed inhibitors could temporarily reduce PTPN22 activity and release a controlled immune response against tumors.

The strategy is technically challenging because protein tyrosine phosphatases have highly conserved catalytic regions that bind phosphate-containing substrates. Compounds designed only for the active site can therefore struggle to distinguish one phosphatase from another, increasing the risk of unwanted effects. Many phosphatase inhibitors also have difficulty entering cells, remaining stable in biological environments or reaching sufficient concentrations in tissues. Zhang’s team pursued a different design principle: instead of relying solely on the catalytic pocket, the researchers sought molecules that could engage both the active site and neighboring structural pockets unique to the target enzyme. This approach is intended to improve binding strength and selectivity by exploiting a larger molecular surface. It also reflects a broader shift in drug discovery, in which researchers use adjacent or “allosteric” regions around an enzyme’s catalytic center to create inhibitors with more favorable biological behavior.

The Purdue researchers began with quinolone-3-carboxylic acid, a chemical scaffold identified as a PTPN22 inhibitor from an in-house collection of drug-like small molecules. A chemical scaffold is the core framework of a compound, providing the architecture onto which additional functional groups can be attached. The team used a fragment-based focused library approach, linking carefully selected molecular fragments to different positions on the quinolone core. Such fragments are relatively small chemical units chosen for their ability to establish specific interactions with a protein, including hydrogen bonds, electrostatic attractions and hydrophobic contacts. By systematically modifying the scaffold, the scientists searched for structures that would occupy the catalytic site while extending into nearby pockets. This process produced L-32, a quinolone-based inhibitor with stronger activity and improved selectivity compared with the group’s previous derivatives.

Laboratory testing indicated that L-32 could inhibit PTPN22 and retain activity in cellular systems, an important distinction in medicinal chemistry. A compound may bind effectively to a purified enzyme but fail inside cells because it cannot cross the cell membrane, is rapidly degraded, binds nonspecifically to other proteins or is pumped out by cellular transporters. Cellular efficacy suggests that at least part of the compound’s biochemical activity survives the complex environment of a living cell. The researchers also evaluated characteristics related to pharmacokinetics, the study of how a compound is absorbed, distributed, metabolized and eliminated by the body. According to Zhang, L-32 demonstrated a more favorable pharmacokinetic profile than earlier molecules, including oral bioavailability. An orally bioavailable drug can be absorbed through the gastrointestinal tract, a property that may simplify treatment compared with medicines requiring injection, although further optimization and safety testing would be needed before any clinical use could be considered.

The compound was then examined in syngeneic MC38 tumor models, systems in which cancer cells and immune cells come from genetically compatible animals. These models are particularly useful for immunotherapy research because they preserve interactions between the tumor and an intact immune system, unlike some models that rely on severely immune-deficient animals. In the Purdue study, L-32 was reported to reduce MC38 tumor growth in vivo more effectively than earlier compounds. The researchers attributed this effect to the promotion of antitumor immunity, involving the coordinated activity of innate and adaptive immune defenses. Innate immune cells provide rapid, broad responses to abnormal tissue, while adaptive immune cells, including T lymphocytes, can recognize specific tumor-associated antigens and develop more durable responses. By inhibiting an immune checkpoint within signaling pathways rather than directly poisoning cancer cells, L-32 represents an immunomodulatory approach: its aim is to improve the body’s capacity to attack tumors rather than act solely as a conventional cytotoxic agent.

The findings also illustrate why PTPN22 has remained an intriguing but underdeveloped therapeutic target. The biological rationale for inhibiting the enzyme has been strengthened by genetic and immunological evidence, yet the field has lacked high-quality chemical tools capable of probing the target reliably. Selective inhibitors are essential not only as potential drugs but also as research instruments. They allow scientists to determine which effects result specifically from blocking PTPN22 and which arise from unintended interactions with related phosphatases. L-32’s reported combination of biochemical potency, selectivity and cellular activity could therefore help clarify how PTPN22 influences immune-cell signaling within tumors. At the same time, the relationship between immune stimulation and autoimmunity will require close attention. Because PTPN22 helps regulate immune tolerance, prolonged or excessive inhibition could theoretically increase inflammatory reactions or autoimmune complications. The compound’s therapeutic window, or range between effective and toxic doses, will be a central question in future studies.

Zhang’s team plans to refine L-32 and conduct additional tests of its efficacy in vivo. The researchers are particularly interested in cancers that are difficult to treat with existing approaches, including pancreatic and liver cancers, as well as tumors that have become resistant to current immunotherapies. Resistance can develop when tumors exclude immune cells, suppress antigen presentation, alter inflammatory signaling or create a microenvironment that disables T cells and other immune effectors. A PTPN22 inhibitor could potentially be evaluated as a standalone treatment or in combination with established immunotherapies, although the appropriate combinations and dosing schedules remain unknown. Before such possibilities can be assessed in humans, researchers must establish detailed toxicology profiles, confirm reproducible pharmacokinetics, study how the compound behaves across different tumor types and determine whether its immune effects are sufficiently selective. Animal results, even when encouraging, do not guarantee clinical benefit.

The research has been published in the Journal of Medicinal Chemistry under the title “A Potent and Selective Quinolone-Based PTPN22 Inhibitor with Improved Immunotherapeutic Activity.” Zhang and his collaborators have disclosed the quinolone-based PTPN22 inhibitors, including L-32, to the Purdue Innovates Office of Technology Commercialization, which has applied for patent protection through the U.S. Patent and Trademark Office. The intellectual property is available for potential development or commercialization through Purdue’s licensing program. The study was supported in part by the National Institutes of Health and the Robert C. and Charlotte Anderson Chair Endowment. While L-32 remains an experimental lead compound, its development adds momentum to efforts to drug protein tyrosine phosphatases and suggests that targeting a previously underexplored immune regulator may eventually broaden the range of strategies available against cancer.

Subject of Research: Development of L-32, a quinolone-based small-molecule inhibitor of PTPN22 for cancer immunotherapy.

Article Title: A Potent and Selective Quinolone-Based PTPN22 Inhibitor with Improved Immunotherapeutic Activity

Web References: Purdue University College of Pharmacy; Purdue Institute for Cancer Research; Purdue Institute for Drug Discovery; Purdue Innovates Office of Technology Commercialization; Journal of Medicinal Chemistry article page: https://pubs.acs.org/jmcmar/article/69/14/16401/5172625/A-Potent-and-Selective-Quinolone-Based-PTPN22

References: Journal of Medicinal Chemistry, DOI: 10.1021/acs.jmedchem.5c03467

Image Credits: Purdue University photo/Ashley Jensen

Keywords: PTPN22, L-32, cancer immunotherapy, small-molecule inhibitors, quinolone-based inhibitors, protein tyrosine phosphatases, antitumor immunity, drug discovery, cancer research, pancreatic cancer, liver cancer, MC38 tumor model

The innovation pivots on the core technology of desorption electrospray ionization mass spectrometry (DESI-MS), a method pioneered at Purdue nearly two decades ago. DESI-MS facilitates rapid chemical analysis by ionizing molecules directly from surfaces under ambient conditions, minimizing sample preparation and volume. The platform leverages this technique’s speed and sensitivity to enable automated, high-throughput screening of synthetic reaction products, followed immediately by their biological evaluation without the need for extensive purification or manual intervention. This capability creates an unprecedented experimental cadence, wherein chemical space can be explored iteratively and dynamically within a single experimental narrative.

Historically, drug discovery operated as a segmented assembly line. Chemists synthesized compounds, biologists conducted efficacy assays, and analytical chemists characterized molecular structures in a disconnected, time-consuming sequence. This fragmented paradigm often introduced weeks of lag time between cycles, significantly impeding rapid candidate refinement. The PICR team identified this bottleneck early in their development, aiming to collapse these distinct stages into a unified, automated pipeline. By interfacing synthesis, biological screening, and mass spectrometric validation, they have created a real-time feedback loop where synthetic strategies can be adjusted on-the-fly informed directly by biological outcomes and structural verification.

One of the most compelling applications demonstrated by the team involved a notoriously refractory cancer-associated enzyme. Traditional approaches had subjected this target to years of incremental work, with limited success and unclear mechanistic insights. Utilizing the new platform, researchers rapidly screened vast chemical libraries and identified that a frequently assumed active compound was not engaging the target as previously believed. This revelation empowered the team to pivot direction swiftly, avoiding years of unproductive research effort and instead focusing resources on stronger candidate molecules unveiled by their integrated screening process.

Nicolás Morato, the lead author of the study and research assistant professor, emphasized that the platform is much more than a tool for accelerating chemistry—it is a transformative approach that converges data generation, synthesis, and biological evaluation. The system supports the generation of voluminous, high-fidelity experimental data critical for training and improving artificial intelligence models aimed at drug discovery. Morato notes that the symbiosis between rapid experimental throughput and AI prediction cycles stands to reshape paradigms in precision oncology by enabling a virtuous cycle of machine learning-driven hypothesis generation and rapid empirical validation.

Complementing the technological innovation, R. Graham Cooks, a visionary chemist and one of DESI’s original inventors, highlighted the vital role mass spectrometry plays in modern drug discovery workflows. Major pharmaceutical entities now depend heavily on mass spectrometry for compound characterization and reaction monitoring, yet the Achilles’ heel remains speed. The team’s novel system surmounts this limitation by automating multiple discrete processes—chemical reaction monitoring, product validation, and biological assay—into a single, streamlined platform. This integration yields a quantum leap forward in throughput, compressing timelines that traditionally stretched over weeks into a few hours per discovery cycle.

Beyond its impact on drug candidate screening, the technology has profound implications for precision oncology diagnostics and surgical interventions. The capacity for intraoperative mass spectrometric analysis allows surgeons to identify tumor margins and metabolite profiles in real time, tailoring surgical decisions with unprecedented molecular precision. This diagnostic agility not only enhances treatment outcomes but also reflects the broader transformative potential of advanced mass spectrometry technologies in clinical oncology.

The platform’s development was catalyzed through federal support by the National Center for Advancing Translational Sciences under its ASPIRE Cooperative Research Program, which aims to bridge translational gaps in early drug development via automation and innovative data analytics. The Purdue group’s approach exemplifies how academic-industry-government collaborations can generate platform technologies that transcend traditional disciplinary boundaries. The realization of such integrated, scalable workflows highlights a new frontier in medicinal chemistry research, accelerating the identification of therapeutically viable molecules with enhanced confidence.

Functionally, the platform’s ultrahigh-throughput capability derives from leveraging minuscule reaction volumes coupled with robust data acquisition and processing algorithms. Automated liquid handling streams chemical reactions at microscale, while DESI-MS instantaneously captures and characterizes reaction mixtures post-synthesis. Biological assays incorporate direct-to-biology methods, bypassing purification bottlenecks, and allowing functional testing to proceed rapidly on complex mixtures. This orchestrated workflow facilitates iterative cycles of design, synthesis, testing, and optimization within a compressed timeframe previously unattainable in standard laboratory settings.

The transformative implications for cancer drug discovery are immense. With emergent genomic, proteomic, and AI-driven methodologies identifying an expanding repertoire of novel cancer targets, the bottleneck lies increasingly in experimental validation and drug candidate progression. By effectively aligning experimental throughput with computational model demands, Purdue’s platform accelerates the translation of in silico predictions into verified therapeutic molecules. This has the profound potential to expedite clinical pipelines, delivering promising cancer treatments to patients with critical speed.

Morato’s personal connection to cancer research underscores the team’s commitment—the impetus for faster, more precise tools is not abstract but deeply human. As early-stage drug discovery shifts from prolonged, iterative cycles into agile, data-rich workflows, technologies such as this DESI-MS platform will be instrumental in transforming how we confront cancer’s complexity. The platform’s proven ability to marshal multidisciplinary expertise, automation, and cutting-edge analytical chemistry sets a new benchmark for integrated drug discovery innovation.

In sum, Purdue’s ultrahigh-throughput DESI-MS platform heralds a paradigm shift for oncology drug discovery. By seamlessly harmonizing synthesis, screening, and mass spectrometric analysis into a cohesive, rapid process, it dismantles long-standing barriers imposed by disconnected workflows. This breakthrough not only accelerates the identification of effective cancer therapies but also paves the way for AI-enhanced precision medicine—a critical leap for one of the most formidable challenges in biomedical science today.

Subject of Research: Not applicable

Article Title: Early-stage drug discovery in a new-generation ultrahigh-throughput mass spectrometry platform

News Publication Date: 2-Jun-2026

Web References:

• Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.253655212
• Purdue Institute for Cancer Research: https://cancer.research.purdue.edu/
• ASPIRE Program: https://ncats.nih.gov/aspire

References:
Morato N., et al. Early-stage drug discovery in a new-generation ultrahigh-throughput mass spectrometry platform. Proc Natl Acad Sci U S A. 2026 Jun 2; doi:10.1073/pnas.253655212

Image Credits: Purdue University photo by Charles Jischke

Keywords: Drug discovery, High throughput screening, Mass spectrometry, Electrospray ionization, Cancer treatments

One of the highlighted projects is spearheaded by Distinguished Professor Andrew Mesecar, a leader in cancer structural biology and director of the Purdue Institute for Cancer Research. His work focuses on developing potent inhibitors targeting Ubiquitin Specific Protease 7 (USP7), a human enzyme implicated in hepatocellular carcinoma (HCC), the most prevalent form of liver cancer worldwide. Mesecar’s approach is notable for its selectivity: the compounds under development inhibit USP7 through a unique binding mechanism distinct from the enzyme’s catalytic site, which sets them apart from existing inhibitors and promises reduced off-target effects, a critical hurdle in drug development.

The significance of Mesecar’s research lies not only in its molecular specificity but also in the broader public health context. HCC presents formidable challenges, with rising incidence rates and a dearth of effective therapies leading to high mortality worldwide. By advancing novel, patent-backed compounds that selectively shut down USP7 activity, Mesecar and his team aim to pioneer a new class of therapeutics that could improve clinical outcomes and reduce treatment-related economic burdens. The Trask Innovation Fund award will support the synthesis of refined molecules with enhanced drug-like properties and higher efficacy across diverse HCC cell lines, paving the way toward preclinical validation.

In parallel, the College of Engineering’s Jerry M. and Lynda T. Engelhardt Professor Pablo Zavattieri is leading an innovative project to develop a reconfigurable and navigable waterway barrier (RNWB) designed to tackle saltwater intrusion in the Panama Canal. This effort responds to critical environmental and economic pressures fueled by climate change, increased water use resulting from Neopanamax vessels, and dwindling freshwater reserves in Gatun Lake, which is essential for the canal’s operation. Saltwater contamination threatens both potable water supplies and the canal’s operational efficiency, posing risks to global maritime trade.

Zavattieri’s RNWB leverages advanced materials engineered at Purdue to prevent the mixing of saltwater and freshwater during ship transits through the canal. The design is patent-pending and represents a sophisticated solution that balances ecological preservation with economic imperatives. By effectively isolating saltwater, the barrier could sustain freshwater availability, maintain canal throughput, and mitigate revenue losses tied to reduced transit capacity. This technology has garnered strong interest from the Panama Canal Authority (ACP), with which Purdue maintains a collaborative relationship bolstered by connections such as former ACP Vice President and Purdue alumnus Luis Alfaro.

Central to the RNWB project is the plan to use the Trask funding for a six-month intensive phase that will refine barrier design, fabricate a proof-of-concept prototype, and conduct controlled testing within Purdue’s facilities. These steps are critical to de-risk the technology, demonstrate feasibility, and lay the foundation for commercial partnerships. Discussions with ACP have already explored viable business models, including startup formation and licensing pathways, highlighting the translational impact of the research. Successful deployment of the RNWB could revolutionize how critical waterways address saltwater intrusion globally, extending Purdue’s legacy of practical civil engineering solutions.

The Trask Innovation Fund itself plays an instrumental role in bridging what innovators call the “valley of death” — the often-prolonged gap between academic invention and marketable product. Managed by Purdue Innovates Incubator, the fund provides crucial resources allowing researchers to generate data, build prototypes, validate concepts, and advance commercialization strategies. Its support complements a broader ecosystem fostering entrepreneurial activities, including customer discovery, regulatory guidance, team building, and business modeling. As fund manager Matt Dressler explains, this financial and programmatic support accelerates the translation of early-stage discoveries, making them attractive to industry partners and investors.

Purdue Innovates Incubator serves as the gateway to these innovation resources, offering Purdue-affiliated inventors and entrepreneurs valuable programming and mentorship opportunities. By aligning technical research with strategic business acumen, the incubator enhances the likelihood that transformative ideas reach the marketplace and create tangible societal benefits. The incubator team actively encourages alumni and community members to contribute as mentors, creating a dynamic network that bridges academia and industry.

Purdue University’s stature as a leading public research institution bolsters the visibility and impact of projects like those funded by the Trask Innovation Fund. Ranked among the top 10 public universities nationwide, Purdue harnesses a vast and diverse community of over 107,000 students and multiple campuses to foster interdisciplinary research excellence. Its sustained commitment to affordability, exemplified by a 14-year tuition freeze at its main campus, reflects a broader vision to democratize access to knowledge and innovation.

The innovative scope of the USP7 inhibitors offers promising advancements in biomedical science, specifically targeting the mechanistic underpinnings of cancer proliferation. By focusing on an allosteric site distinct from active centers commonly targeted by drugs, Mesecar’s compounds exploit novel inhibitory pathways, potentially minimizing adverse interactions seen in existing treatments. Such precision medicine approaches are critical in addressing complex diseases like HCC, where heterogeneity and drug resistance complicate therapy.

On the environmental engineering front, Zavattieri’s RNWB represents a significant leap in infrastructure design, combining material science and civil engineering principles with real-world environmental challenges. The dynamic and reconfigurable nature of the barrier allows it to adapt to the canal’s operational requirements and variable hydrological conditions. By enabling navigable passage for Neopanamax vessels without compromising freshwater stores, the RNWB could substantially enhance the canal’s resilience to climate-induced stresses and escalating maritime demands.

These projects epitomize the convergence of scientific inquiry and practical application, demonstrating how university research can address global challenges in health and environmental management. The strategic use of intellectual property protection ensures that these innovations retain commercial viability while preserving the incentives for continued academic exploration and collaboration.

Furthermore, the emphasis on commercialization pathways illustrates a holistic approach to research translation, where technical development is integrated with market analysis, stakeholder engagement, and scalable business models. This synergy amplifies the potential impact of Purdue’s innovations, positioning them for success not only in the lab but also in real-world deployment.

As the academic year progresses, the outcomes of these projects will likely inform broader discussions on the role of university-driven innovation funds and incubators in accelerating the pace at which cutting-edge discoveries improve human health and environmental sustainability. By fostering collaboration across disciplines and engaging with global partners such as the Panama Canal Authority, Purdue sets a compelling model for impactful, solution-oriented research.

In summary, the Trask Innovation Fund’s support of Andrew Mesecar’s novel USP7 inhibitors and Pablo Zavattieri’s reconfigurable waterway barrier exemplifies the power of targeted investment in early-stage technologies. Both endeavors harness Purdue’s rich expertise and resources to confront pressing issues—cancer therapeutics and freshwater conservation—with transformative potential. As these projects advance toward commercialization, they underscore the vital role that academic innovation ecosystems play in shaping the future of science, technology, and global well-being.

Subject of Research:
Cancer therapeutics targeting USP7 enzyme for hepatocellular carcinoma treatment; Reconfigurable waterway barrier technology addressing saltwater intrusion in critical maritime infrastructure.

Article Title:
Purdue Innovates with Novel Cancer Therapeutics and Waterway Barrier Technologies Backed by Trask Innovation Fund

News Publication Date:
Spring 2025

Web References:

• Purdue Innovates Trask Innovation Fund: https://purdueinnovates.org/incubator/trask-innovation-fund/
• Purdue Institute for Cancer Research: https://www.purdue.edu/cancer-research/
• Lyles School of Civil and Construction Engineering: https://engineering.purdue.edu/CCE
• Purdue Innovates Incubator: https://purdueinnovates.org/incubator/

Image Credits:
Purdue University photo/Nelson Pachao Morbitzer

Keywords:
Research funding, Cancer, Liver cancer, Cancer medication, Cancer treatments, Water management, Freshwater resources, Man made structures, Civil engineering, Transportation infrastructure