ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy

  • Cell Rep Med. 2025 Sep 16;6(9):102336. doi: 10.1016/j.xcrm.2025.102336.
Songnan Wang  1 ,  Randolph M Johnson  2 ,  Jacqueline A Carozza  3 ,  Daniel Fernandez  4 ,  Jan Scicinski  2 ,  Neil A Verity  2 ,  Rachel Mardjuki  3 ,  Xujun Cao  5 ,  Yingjie Guo  3 ,  Jacqueline Papkoff  2 ,  Nigel Ray  2 ,  Lingyin Li  6
Affiliations
  • 1. Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA.
  • 2. Department of Research and Development, Angarus Therapeutics, Inc., Portola Valley, CA 94028, USA.
  • 3. Arc Institute, Palo Alto, CA 94304, USA.
  • 4. Macromolecular Structure Group, Nucleus at ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • 5. ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
  • 6. Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: [email protected].
PMID: 40914167 DOI: 10.1016/j.xcrm.2025.102336
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.

Keywords
STING agonist; breast cancer; colorectal cancer; glioblastoma; immunotransmitter; pancreatic cancer.
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