Cancer immunotherapy seeks to harness the immune system to target and eliminate malignant cells. However, immune suppression within the tumor microenvironment poses a major challenge, blunting T-cell activation and allowing cancer cells to evade immune detection. Diacylglycerol Kinase α (DGKα) is a key enzyme that suppresses T-cell receptor signaling, limiting effective anti-tumor responses. Although reversible DGK inhibitors have been explored, their short duration of action and poor isoform selectivity have constrained their clinical impact. These agents often require frequent dosing and may produce off-target effects, making it difficult to achieve sustained immune activation.
This technology introduces a novel class of naphthyridinone-based small molecules that irreversibly inhibit DGKα through covalent binding. Each molecule features a sulfonyl triazole electrophilic warhead designed to target lysine and tyrosine residues in the DGKα catalytic domain. By forming a covalent bond, these compounds achieve long-lasting inhibition of DGKα, restoring T-cell receptor signaling and enhancing immune activation. The inhibitors have been optimized using sulfur-triazole exchange (SuTEx) chemistry to achieve a balance between potency and selectivity while minimizing off-target reactivity. These compounds exhibit potential allosteric binding and isoform selectivity, and they are suitable for systemic administration in cancer immunotherapy. In preclinical models, they have shown promise for treating solid tumors such as melanoma and glioblastoma, as well as boosting antiviral immune responses.
Provisional US patent application filed 04/09/2025