9nir

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

spinqualitylabelsall models 9nir, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9nir is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.7Å Ligands: A1BYU, BMA, CA, CL, NAG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ENPP3_HUMAN Cleaves a variety of phosphodiester and phosphosulfate bonds including deoxynucleotides, nucleotide sugars, and NAD. Publication Abstract from PubMed 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. ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy.,Wang S, Johnson RM, Carozza JA, Fernandez D, Scicinski J, Verity NA, Mardjuki R, Cao X, Guo Y, Papkoff J, Ray N, Li L Cell Rep Med. 2025 Sep 16;6(9):102336. doi: 10.1016/j.xcrm.2025.102336. Epub 2025 , Sep 5. PMID:40914167 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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