Journal Article Preprint Epublish 1 citation
PubMed: 40475652 DOI: 10.1101/2025.05.18.654655
ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy.
bioRxiv
Authors: Randolph M Johnson, Songnan Wang, Jacqueline A Carozza, Daniel Fernandez, Jan Scicinski, Neil A Verity, Rachel Mardjuki, Xujun Cao, Jacqueline Papkoff, Nigel Ray, Lingyin Li
Affiliations
- Department of Research and Development, Angarus Therapeutics, Inc. Portola Valley, CA 94028, USA.
- Department of Biochemistry, Stanford University; Stanford, CA 94305, USA.
- ChEM-H Institute, Stanford University; Stanford, CA94305, USA.
- Arc Institute; Palo Alto, CA 94304, USA.
- Nucleus at ChEM-H, Stanford University; Stanford, CA 94305, USA.
- Department of Chemistry, Stanford University; Stanford, CA 94305, USA.
Abstract
Only one in five patients is estimated to respond to immune checkpoint inhibitors, which primarily target adaptive immunity. To date, no FDA-approved immunotherapies directly activate the innate anti-cancer immunity-an essential driver of lymphocyte recruitment and potentiator of responses to existing cancer immunotherapies. ENPP1, the dominant hydrolase that degrades extracellular cGAMP and suppresses downstream STING-mediated innate immune signaling, has emerged as a promising therapeutic 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 and synergizes with ionizing radiation, anti-PD-L1 and anti-PD-1, and a DNA damaging agent to produce robust anti-tumor and anti-metastatic effects across multiple syngeneic mouse tumor models, all without detectable toxicity. Conceptually, this work establishes that a noncovalent small molecule inhibitor of ENPP1 with ultralong drug-target engagement offers a safe and precise strategy to activate STING within tumors, fulfilling an unmet need of innate immunotherapies in cancer.
MeSH
Pharmaceutical Preparations, Neoplasms, Therapeutics