| First Author | Wang S | Year | 2025 |
| Journal | Cell Rep Med | Volume | 6 |
| Issue | 9 | Pages | 102336 |
| PubMed ID | 40914167 | Mgi Jnum | J:382876 |
| Mgi Id | MGI:8247659 | Doi | 10.1016/j.xcrm.2025.102336 |
| Citation | Wang S, et al. (2025) ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. Cell Rep Med 6(9):102336 |
| abstractText | Only one in five patients respond to immune checkpoint inhibitors, which primarily target adaptive immunity. Ectonucleotide pyrophosphatase/phophodiesterase 1 (ENPP1), the dominant hydrolase of 2'3'-cyclic-GMP-AMP (cGAMP) that suppresses downstream stimulator of interferon genes (STING) signaling, has emerged as a promising innate immunotherapy target. However, existing ENPP1 inhibitors have been optimized for prolonged systemic residence time rather than effective target inhibition within tumors. Here, we report the characterization of STF-1623, a highly potent ENPP1 inhibitor with an exceptionally long tumor residence time despite rapid systemic clearance, enabled by its high ENPP1 binding affinity and slow dissociation rate. We show that membrane-bound ENPP1 on tumor cells, not the abundant soluble ENPP1 in serum, drives tumor progression. Consequently, STF-1623 unleashes anti-tumor immunity to produce robust anti-tumor and anti-metastatic effects across multiple tumor models. Conceptually, this work establishes a noncovalent small-molecule inhibitor of ENPP1 with ultralong drug-target engagement as a safe and precise strategy to activate STING within tumors. |
