9NIR

Human Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) inhibitor complex

This is a non-PDB format compatible entry.

Summary for 9NIR

• Entry DOI: 10.2210/pdb9nir/pdb
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase family member 3, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: ec 3.6.1.9, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 99555.42

Authors

Fernandez, D.,Li, L.,Carozza, J.A. (deposition date: 2025-02-26, release date: 2026-01-07)

Primary citation

Wang, S.,Johnson, R.M.,Carozza, J.A.,Fernandez, D.,Scicinski, J.,Verity, N.A.,Mardjuki, R.,Cao, X.,Guo, Y.,Papkoff, J.,Ray, N.,Li, L.
ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy.
Cell Rep Med, 6:102336-102336, 2025

PubMed Abstract: 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.

PubMed: 40914167
DOI: 10.1016/j.xcrm.2025.102336

Experimental method

X-RAY DIFFRACTION (2.7 Å)