Boronic acid ENPP1 inhibitors stay active across tumor-relevant pH
- ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
- Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
- Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.
💡 Points
Phosphate- and phosphonate-type ENPP1 binders have always struggled with permeability and exposure, so swapping in a boronic acid zinc binder is a cleaner route. Designing for acidic-pH activity is the smart part, since that is where the enzyme works. Single-agent efficacy by IP dosing is modest, so oral exposure and boronic acid stability are my next questions.
Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗