2. Academic Validation
  3. ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy

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

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: lingyinl@stanford.edu.
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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