Sulfonyl-triazole activators for cell-selective glycolysis enhancement in cancer and Parkinson’s disease

Background

Cellular metabolism is a central regulator of immune cell function and neuronal survival, making it a promising therapeutic target in both cancer and neurodegenerative disease. In solid tumors, tumor-infiltrating lymphocytes (TILs) frequently succumb to metabolic exhaustion due to the nutrient-depleted and immunosuppressive microenvironment, reducing the efficacy of immune checkpoint inhibitors and T cell–based therapies. In Parkinson’s disease, degeneration of dopaminergic neurons is linked to chronic bioenergetic failure, a process unaddressed by current symptomatic treatments. These challenges highlight the urgent need for strategies that selectively and durably boost glycolytic flux in specific cell populations to restore function and improve disease outcomes.

Current interventions rely heavily on non-specific cytokines, dietary supplements, or immune checkpoint therapies, which offer limited control over cellular metabolism and often cause systemic side effects. Meanwhile, neuroprotective strategies have struggled to meaningfully impact neuronal metabolism due to poor brain penetration and lack of enzyme-specific targeting. Small-molecule attempts to modulate glycolysis have so far fallen short due to instability in physiological conditions and insufficient target specificity, constraining their translational potential.

Technology overview

This technology introduces a novel class of small-molecule sulfonyl-triazoles that covalently activate phosphofructokinase liver-type (PFKL)—a key rate-limiting enzyme in glycolysis. These compounds selectively enhance glycolytic flux in TILs, reversing immunosuppression and boosting antitumor responses. Prototype molecules have demonstrated proteome-wide selectivity and target engagement in purified recombinant PFKL, PFKM, and PFKP isoforms. Early studies also show that these compounds can directly impair tumor cell proliferation, suggesting dual utility in immune enhancement and cancer targeting.

By covalently binding to PFKL, the activators provide durable enzymatic activation without requiring exogenous cytokines or genetic modification. The sulfonyl-triazole scaffold offers a tunable platform, with opportunities to improve aqueous stability, tissue distribution, and blood-brain barrier permeability through strategic chemical modifications. This cell-targeted metabolic reprogramming approach represents a promising adjunct to existing cancer immunotherapies and a potential breakthrough in neuroprotective drug development.

Benefits

Covalently activates PFKL to boost glycolysis in targeted cells
Enhances TIL metabolism and antitumor immune responses
High selectivity avoids off-target metabolic effects
Prototype compounds inhibit tumor proliferation directly
Tunable chemistry supports improved stability and CNS targeting

Applications

Cancer immunotherapy adjunct
Neuroprotective therapy for Parkinson’s disease
Metabolic reprogramming agents
Immune cell metabolic enhancers
Brain-penetrant enzyme activators

Opportunity

Addresses critical limitations in TIL exhaustion and neuronal energy failure
Offers complementary mechanism to checkpoint blockade and adoptive T cell therapies
Expandable platform for metabolic drug development across multiple disease areas
Available for exclusive licensing