The strategy, reported in Nature Chemical Biology, centers on an enzyme called PFKL, or the liver isoform of phosphofructokinase. PFKL regulates a critical step in glycolysis, the biochemical pathway that converts glucose into energy and metabolic building blocks. Tumors frequently rely heavily on glycolysis, even when oxygen is available, a phenomenon associated with the Warburg effect. Instead of inhibiting this pathway, the researchers designed a molecule called XJ-4-85 that activates PFKL and accelerates glucose breakdown inside cancer cells.

That metabolic acceleration is only half of the drug’s mechanism. Once XJ-4-85 binds to PFKL, the compound releases a chemical payload that interferes with CPT2, an enzyme required for mitochondrial fatty-acid oxidation. CPT2 helps transport fatty-acid-derived molecules through the mitochondrial system so they can be broken down to produce energy. By disrupting CPT2, the drug removes a major backup fuel source precisely when the cancer cell is consuming glucose at an unusually high rate.

Structural studies helped reveal how the compound operates. Cryo-electron microscopy showed XJ-4-85 associated with PFKL at two sites, identified as K677 and K315. These interactions stabilize an activated form of the enzyme, increasing glycolytic activity. The molecule is also designed to undergo a chemical transformation after binding, releasing an electrophilic payload that can act on its second target. This architecture allows the same small molecule to combine selective protein recognition with a separate, covalent mechanism of enzyme disruption.

The researchers describe the approach as a “two-headed dragon” because it attacks cancer metabolism from opposite directions. Increasing glycolysis raises the demand for glucose and places additional pressure on the cell’s metabolic machinery. Blocking fatty-acid oxidation prevents the cell from switching to lipids when glucose metabolism becomes insufficient. With both pathways compromised, cancer cells may be unable to maintain adequate energy production, redox balance and biosynthetic capacity, leaving them vulnerable to metabolic collapse.

In laboratory experiments, the compound showed activity against human melanoma, leukemia, breast cancer, lung cancer, liver cancer and neuroblastoma cells. In mouse models of an aggressive melanoma, treatment caused extensive cancer-cell death and suppressed tumor growth. The researchers reported that noncancerous cells were less affected under the conditions tested, suggesting that the compound may exploit differences between tumor and normal-cell metabolism. However, this selectivity remains an experimental observation rather than evidence of safety in people.

The work represents a chemical alternative to antibody-drug conjugates, which use antibodies to recognize markers on cancer cells and deliver toxic payloads. Antibodies can be highly selective, but their large size generally limits them to targets accessible on the cell surface. Small molecules such as XJ-4-85 can enter cells and reach intracellular proteins, including metabolic enzymes. They are also potentially simpler to manufacture and modify, although achieving reliable tumor selectivity and controlling off-target chemical reactions remain major challenges.

The researchers call this broader class of compounds electrophile-drug conjugates, or EDCs. Unlike conventional drug conjugates that may simply carry a toxin to a target cell, EDCs are designed to use a recognition element to engage a protein and then release a reactive component capable of forming a lasting chemical interaction with another target. The concept could eventually be adapted beyond cancer, but its usefulness will depend on whether scientists can precisely control where and when the electrophilic payload is released.

The findings are still at an early preclinical stage. The drug has been tested in cultured cells and animal models, not in human patients, and further studies will be needed to evaluate dosing, distribution, toxicity, immune effects and the possibility of resistance. Cancer cells can rewire their metabolism, and tumors are biologically diverse, so the treatment may not work equally well across all cancers. Even so, the study offers a striking change in direction: rather than starving tumors by cutting off glucose, researchers are attempting to make cancer cells consume more sugar while closing the metabolic escape route provided by fat.

Subject of Research: Animals

Article Title: A Covalent PFKL Activator Suppresses Tumor Growth

News Publication Date: 5-Aug-2026

Web References: https://www.nature.com/articles/s41589-026-02289-9; https://doi.org/10.1038/s41589-026-02289-9

References: Nature Chemical Biology, “A Covalent PFKL Activator Suppresses Tumor Growth,” DOI: 10.1038/s41589-026-02289-9

Image Credits: Eric Lynch, University of Washington, and Xiaoding Jiang, University of Texas at Austin

Keywords: cancer metabolism, cancer treatment, cancer medication, chemotherapy, melanoma, glycolysis, PFKL, CPT2, fatty-acid metabolism, electrophile-drug conjugates, drug discovery, experimental cancer therapy

At the core of this breakthrough are multifunctional copper-based nano-PROTACs, referred to as CHNDs. These nanoscale agents seamlessly integrate targeted protein degradation technology with copper-mediated cytotoxicity. The molecular target of this system is hexokinase 2 (HK-2), a pivotal enzyme responsible for initiating glycolysis by phosphorylating glucose. HK-2 is heavily exploited by rapidly proliferating cancer cells to sustain their elevated metabolic demands. Unlike conventional inhibitors, CHNDs harness the power of proteolysis targeting chimeras (PROTACs) to degrade HK-2, thereby effectively precluding the enzyme’s compensatory activation and quelling glycolytic flux with superior potency.

The initial step in the researchers’ design involved engineering PEI-based HK-2 degraders, dubbed PHDs. These molecular constructs are composed of a 3-bromopyruvate moiety—a covalent warhead that specifically binds to HK-2—linked to a thalidomide derivative, which acts as a recruiting ligand for the cereblon E3 ubiquitin ligase. This architectural assembly orchestrates proximity-induced ubiquitination, guiding HK-2 to the proteasome for rapid degradation. Experimental application in murine 4T1 breast cancer and CT26 colon cancer cell models confirmed that PHD treatment resulted in a significant diminution of HK-2 protein levels, reducing expression by over 40%, which translated into marked inhibition of glycolytic activity.

Building upon this foundation, the research team developed the CHND platform by adorning copper-based metal–organic framework (MOF) nanoparticles with polyethylene glycol (PEG)-linked PHDs. This design ensures nanoparticle stability within the bloodstream while enabling the preferential release of bioactive components in the acidic and glutathione-rich microenvironment characteristic of tumors. Upon accumulation in cancerous tissue, the CHNDs disassemble, releasing copper ions alongside PEG-PHD conjugates. The liberated PEG-PHDs perpetuate the degradation of HK-2, curtailing glycolysis, while copper ions initiate mitochondrial perturbations. This triggers cuproptosis, a unique form of cell death distinguished by DLAT protein aggregation and disturbance of iron–sulfur cluster proteins critical for mitochondrial function.

Cellular assays vividly demonstrated that CHND treatment surpassed the efficacy of either copper nanoparticles or HK-2 degraders alone. The combinatorial therapy led to pronounced suppression of glycolytic flux and reduced lactate production, key indicators of disrupted energy metabolism. Concurrently, intracellular ATP levels plummeted, reactive oxygen species surged, and mitochondrial membrane potential dissipated, hallmarks of mitochondrial distress. Moreover, DLAT aggregation was amplified, further corroborating the activation of cuproptotic pathways. These multifaceted perturbations showcase the potency of CHNDs in orchestrating dual metabolic inhibition.

Delving deeper into the mechanistic underpinnings, transcriptomic profiling of CHND-treated cancer cells unveiled widespread dysregulation across multiple biological processes. Genes implicated in proteasome activity, ubiquitin-mediated proteolysis, and endoplasmic reticulum protein processing were notably disrupted, indicating substantial disturbance in protein homeostasis. Additionally, pathways governing oxidative stress responses, mitochondrial respiratory chain assembly, and oxidative phosphorylation were profoundly affected, underscoring the comprehensive assault on cellular redox balance and bioenergetics. These transcriptomic insights reinforce the concept that CHNDs execute their antitumor effects by coordinating a simultaneous collapse of metabolic, proteostatic, and redox networks essential for cancer cell survival.

Translating these findings in vivo, the study employed several murine tumor models to evaluate therapeutic efficacy. In orthotopic 4T1 breast cancer models, CHND administration led to a striking 55.3% reduction in tumor volume. Even more compelling, in CT26 colon carcinoma models, tumor inhibition reached a substantial 76.6%, accompanied by a significant extension of median survival from 21 to 29 days. Remarkably, a subset of animals treated with CHNDs survived beyond 100 days, highlighting the potential for durable therapeutic responses. Histopathological analyses of excised tumors corroborated these outcomes by demonstrating pronounced HK-2 depletion, enhanced DLAT aggregation, and elevated indicators of tumor cell apoptosis.

The impact of CHNDs extended beyond primary tumors, revealing promising antimetastatic activity. In a spontaneous lung metastasis model derived from 4T1 breast cancer cells, animals receiving CHND treatment exhibited markedly reduced bioluminescent signals in lung tissue, alongside fewer metastatic nodules upon gross examination. These findings suggest that impairing glycolytic compensation and mitochondrial function collectively stymie not only tumor growth but also metastatic dissemination—an important advantage given the lethality of metastatic disease in clinical oncology.

Importantly, the study situates itself at the intersection of metal-ion cytotoxicity and targeted protein degradation—two therapeutic strategies that have historically advanced along separate tracks. CHNDs embody a novel paradigm by merging these modalities within a single nanoplatform, effectively converting copper from a mere cytotoxic agent to an integral component of a precision metabolic intervention. This synergistic approach capitalizes on the inherent vulnerabilities of cancer metabolism, specifically the reliance on HK-2-driven glycolysis and mitochondrial respiration, pushing cancer cells beyond the limits of metabolic plasticity.

Despite these compelling preclinical results, the path to clinical application will require further investigations. Key challenges include evaluating long-term implications of metal ion accumulation, potential immunogenicity of the metal-organic nanoparticles, pharmacokinetic profiles, and intertumoral heterogeneity that may influence therapeutic response. Additionally, rigorous safety assessments in larger animal models will be critical to address off-target effects and ensure tolerability. Nonetheless, the study’s conceptual advancement sets the stage for future translational efforts aiming to refine and harness integrated metabolic cancer therapies.

As a methodical example of engineering multifunctional nanotherapeutics capable of targeted protein degradation coupled with metal ion-induced cell death, this work heralds a new horizon in precision oncology. The elegant coupling of HK-2 degradation and cuproptosis induction illustrates the power of simultaneous multi-route blockade of cancer metabolism. Such integrative strategies offer hope in overcoming the formidable challenge posed by metabolic adaptability—a hallmark of malignant neoplasms—and may ultimately catalyze the development of next-generation treatments that improve patient outcomes and survival.

In summary, the development of CHNDs exemplifies a landmark advancement in multifunctional nanomedicine, where metabolic inflexibility is exploited for therapeutic gain. By joining copper-triggered mitochondrial stress with the targeted degradation of a glycolytic gatekeeper, this nanoplatform disrupts the core energetic and proteostatic infrastructure required for tumor sustenance. This synergistic assault on malignancy validates the strategy of coupling metal-induced cuproptosis with degradation of glycolytic enzymes as a powerful approach to cancer treatment, offering a promising avenue for future research and clinical translation.

Subject of Research: Not applicable

Article Title: Multifunctional Engineered Metal–Organic Frameworks as Targeted Protein Degraders for Augmenting Cancer Therapy via Hexokinase 2 Degradation and Provoking Cuproptosis

News Publication Date: 31-Mar-2026

Web References: 10.34133/research.1217

Keywords: cuproptosis, cancer metabolism, hexokinase 2, targeted protein degradation, metal–organic frameworks, nanomedicine, glycolysis inhibition, mitochondrial stress, 3-bromopyruvate, copper ions, reactive oxygen species, proteostasis

Triple-negative breast cancer presents a formidable challenge due to its lack of hormone receptors and HER2 expression, effectively eliminating many targeted therapy options available for other breast cancer subtypes. This aggressive malignancy disproportionately affects younger women and is associated with poor prognosis, high rates of recurrence, and widespread metastasis. The molecular intricacies of TNBC have long hindered effective treatment, making the identification of innovative therapeutic targets a crucial priority in oncology research.

The study spearheaded by Dr. Sanjay V. Malhotra, Ph.D., co-director of the Center for Experimental Therapeutics at the OHSU Knight Cancer Institute, elucidates the unique mechanism by which SU212 acts. Unlike traditional orthosteric inhibitors that bind directly to the active site of target enzymes, SU212 operates through a non-orthosteric mode of inhibition. This subtler engagement induces the degradation of ENO1 rather than mere enzymatic blockade, ultimately suppressing tumor growth and metastatic spread in vivo. This level of mechanistic insight lends significant weight to SU212’s potential clinical utility.

Enolase 1 plays a fundamental role in glycolysis, the metabolic pathway by which glucose is converted into energy, a process that cancer cells notoriously upregulate to fuel their rapid proliferation. ENO1 overexpression in cancerous tissues amplifies glycolytic flux, thus contributing to tumor survival and aggressiveness. By targeting ENO1 for degradation, SU212 disrupts this metabolic advantage, effectively impairing the energy homeostasis critical for cancer cell viability and dissemination.

The research team employed humanized mouse models, which are mice engineered to carry human immune cells, thus more accurately replicating the complex interactions between tumor cells and the immune system found in patients. The application of such advanced models enhances the translational relevance of SU212’s efficacy, providing a more precise prediction of its therapeutic potential in humans.

Of notable significance is the molecule’s dual relevance in cancer and metabolic diseases. Since ENO1 is intrinsically linked to glucose metabolism, SU212 might offer distinct advantages for patients battling concurrent metabolic disorders such as diabetes. This intersection is particularly important, given the epidemiological convergence of diabetes and cancer, where hyperglycemia potentially exacerbates tumor progression.

As the preclinical data mounts, the imperative next steps involve advancing SU212 into clinical trials—a process that demands rigorous toxicological profiling, formulation optimization, and substantial investment to navigate regulatory pathways. Dr. Malhotra emphasizes this transition as imperative, underscoring the urgency to translate these findings rapidly from bench to bedside to address the unmet medical needs of TNBC patients.

Beyond triple-negative breast cancer, the modulatory effect of SU212 on ENO1 holds promise for other malignancies characterized by ENO1 dysregulation. These include gliomas, which are aggressive brain tumors; pancreatic ductal adenocarcinoma, notorious for poor prognosis; and thyroid carcinoma. The broad applicability underscores a potential paradigm shift in oncology wherein metabolic vulnerabilities become exploitable therapeutic targets across multiple cancer types.

Dr. Malhotra’s journey from the National Cancer Institute and subsequently Stanford University to OHSU reflects a dedicated pursuit of translating complex molecular insights into tangible clinical solutions. His leadership at OHSU’s Center for Experimental Therapeutics is emblematic of the institution’s commitment to pioneering innovative cancer therapies by bridging rigorous scientific investigation with clinical trial initiation.

The implications of SU212’s mechanism extend beyond direct cytotoxicity. By promoting the degradation of ENO1, there is theoretical potential for SU212 to alleviate the immunosuppressive tumor microenvironment, thus potentially augmenting immune-mediated tumor clearance. This prospect opens avenues for combinatorial therapies integrating SU212 with immuno-oncology agents.

Funding for this research has been robust, harnessing support from prominent institutions including the National Cancer Institute, the National Institute on Aging, the National Heart, Lung, and Blood Institute, alongside the Department of Defense and OHSU’s own Biomedical Innovation Program. This multidisciplinary backing underscores the high relevance and interdisciplinary nature of the project.

All animal studies conducted adhered strictly to ethical standards as overseen by OHSU’s Institutional Animal Care and Use Committee (IACUC), ensuring rigorous review of scientific value, humane treatment, and safety protocols, both for the animal models and research personnel. Compliance with these ethical frameworks is paramount in maintaining research integrity and societal trust.

The advent of SU212 marks a hopeful milestone in the grueling battle against triple-negative breast cancer. While challenges remain in translating these promising findings into approved therapeutics, the precise targeting of cancer metabolism through novel biochemical strategies presents a compelling frontier in oncology. Continued research and clinical validation may soon offer new hope to patients facing this devastating disease.

Subject of Research: People

Article Title: Non-orthosteric inhibition of enolase 1 impedes growth of triple-negative breast cancer

News Publication Date: 7-Nov-2025

Web References:

• OHSU Center for Experimental Therapeutics
• Cell Reports Medicine Article
• Triple-negative breast cancer definition

References:
Malhotra, S.V., et al. (2025). Non-orthosteric inhibition of enolase 1 impedes growth of triple-negative breast cancer. Cell Reports Medicine. DOI: 10.1016/j.xcrm.2025.102451

Image Credits: Oregon Health & Science University

Keywords: Breast cancer, Triple-negative breast cancer, Enolase 1, Cancer metabolism, Metastasis