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We are analyzing https://www.nature.com/articles/s41467-025-59874-0.

Title:
Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors | Nature Communications
Description:
Despite the STING-type-I interferon pathway playing a key role in effective anti-tumor immunity, the therapeutic benefit of direct STING agonists appears limited. In this study, we use several artificial intelligence techniques and patient-based multi-omics data to show that Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), which hydrolyzes STING-activating cyclic GMP-AMP (cGAMP), is a safer and more effective STING-modulating target than direct STING agonism in multiple solid tumors. We then leverage our generative chemistry artificial intelligence-based drug design platform to facilitate the design of ISM5939, an orally bioavailable ENPP1-selective inhibitor capable of stabilizing extracellular cGAMP and activating bystander antigen-presenting cells without inducing either toxic inflammatory cytokine release or tumor-infiltrating T-cell death. In murine syngeneic models across cancer types, ISM5939 synergizes with targeting the PD-1/PD-L1 axis and chemotherapy in suppressing tumor growth with good tolerance. Our findings provide evidence supporting ENPP1 as an innate immune checkpoint across solid tumors and reports an AI design-aided ENPP1 inhibitor, ISM5939, as a cutting-edge STING modulator for cancer therapy, paving a path for immunotherapy advancements. While the STING-type-I interferon pathway plays a key role in anti-tumour immunity, current direct STING agonists have limited therapeutic benefit. Here, the authors identify ENPP1 as a safer and more effective STING-modulating target than direct STING agonism, and use an AI-based drug design platform to design the ENPP1-selective inhibitor ISM5939.
Website Age:
30 years and 10 months (reg. 1994-08-11).

Matching Content Categories {πŸ“š}

  • Science
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Custom-built

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🌠 Phenomenal Traffic: 5M - 10M visitors per month


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$63,100 per month
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Keywords {πŸ”}

enpp, ism, pubmed, cells, cancer, article, google, scholar, cgamp, tumor, fig, data, cas, cell, sting, expression, central, immune, human, tumors, analysis, inhibitor, activation, breast, assay, mice, supp, combination, gse, drug, inhibition, therapy, control, source, patients, pathway, agonists, treated, biological, antitumor, inhibitors, code, potential, response, cat, compounds, discovery, treatment, nature, therapeutic,

Topics {βœ’οΈ}

=\frac{{{\mbox{fold}}-{\mbox{change}}}_{{\mbox{induced}}} }{{{\mbox{fold}}-{\mbox{change}}}_{{\mbox{positive nature portfolio tsp services limited privacy policy springer international publishing advertising rna-seq libraries open targets platform contract research organizations cancer-cell-produced immunotransmitter involved tumor-intrinsic epithelial-mesenchymal transition5 nature 564 nature 573 nature tumor-infiltrating t-cell death reprints patient-based multi-omics data irf3-deficient thp1-dual cells single-cell rna-seq data aging-based dual-purpose disease female balb/cann mice middle research design amp-glo luminescence-based assay reversing epithelial-mesenchymal transition open-label subtype-specific expression programs tumor-bearing mice ablates generative ai-aided discovery ecto-nucleotide pyrophosphatase/phosphodiesterase research trends research progress quanti-lucβ„’ lucia kit messenger cyclic gmp-amp cyclic gmp–amp synthase additional Ο€-Ο€ interactions pre-ranked gene lists boronic acid-based inhibitor radiation-induced anticancer immunity tumor-derived cgamp triggers single-cell rna sequencing efficient physics-based module cutting-edge sting modulator wider therapeutic index post-tumor cell seeding tumor-bearing mice studied single-cell rna-seq single cell rna-seq enpp3 contained tris-hcl

Questions {❓}

  • AI in small-molecule drug discovery: a coming wave?
  • [What are the reasons for patient preference?

Schema {πŸ—ΊοΈ}

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         headline:Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors
         description:Despite the STING-type-I interferon pathway playing a key role in effective anti-tumor immunity, the therapeutic benefit of direct STING agonists appears limited. In this study, we use several artificial intelligence techniques and patient-based multi-omics data to show that Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), which hydrolyzes STING-activating cyclic GMP-AMP (cGAMP), is a safer and more effective STING-modulating target than direct STING agonism in multiple solid tumors. We then leverage our generative chemistry artificial intelligence-based drug design platform to facilitate the design of ISM5939, an orally bioavailable ENPP1-selective inhibitor capable of stabilizing extracellular cGAMP and activating bystander antigen-presenting cells without inducing either toxic inflammatory cytokine release or tumor-infiltrating T-cell death. In murine syngeneic models across cancer types, ISM5939 synergizes with targeting the PD-1/PD-L1 axis and chemotherapy in suppressing tumor growth with good tolerance. Our findings provide evidence supporting ENPP1 as an innate immune checkpoint across solid tumors and reports an AI design-aided ENPP1 inhibitor, ISM5939, as a cutting-edge STING modulator for cancer therapy, paving a path for immunotherapy advancements. While the STING-type-I interferon pathway plays a key role in anti-tumour immunity, current direct STING agonists have limited therapeutic benefit. Here, the authors identify ENPP1 as a safer and more effective STING-modulating target than direct STING agonism, and use an AI-based drug design platform to design the ENPP1-selective inhibitor ISM5939.
         datePublished:2025-05-23T00:00:00Z
         dateModified:2025-05-23T00:00:00Z
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      headline:Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors
      description:Despite the STING-type-I interferon pathway playing a key role in effective anti-tumor immunity, the therapeutic benefit of direct STING agonists appears limited. In this study, we use several artificial intelligence techniques and patient-based multi-omics data to show that Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), which hydrolyzes STING-activating cyclic GMP-AMP (cGAMP), is a safer and more effective STING-modulating target than direct STING agonism in multiple solid tumors. We then leverage our generative chemistry artificial intelligence-based drug design platform to facilitate the design of ISM5939, an orally bioavailable ENPP1-selective inhibitor capable of stabilizing extracellular cGAMP and activating bystander antigen-presenting cells without inducing either toxic inflammatory cytokine release or tumor-infiltrating T-cell death. In murine syngeneic models across cancer types, ISM5939 synergizes with targeting the PD-1/PD-L1 axis and chemotherapy in suppressing tumor growth with good tolerance. Our findings provide evidence supporting ENPP1 as an innate immune checkpoint across solid tumors and reports an AI design-aided ENPP1 inhibitor, ISM5939, as a cutting-edge STING modulator for cancer therapy, paving a path for immunotherapy advancements. While the STING-type-I interferon pathway plays a key role in anti-tumour immunity, current direct STING agonists have limited therapeutic benefit. Here, the authors identify ENPP1 as a safer and more effective STING-modulating target than direct STING agonism, and use an AI-based drug design platform to design the ENPP1-selective inhibitor ISM5939.
      datePublished:2025-05-23T00:00:00Z
      dateModified:2025-05-23T00:00:00Z
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      pageEnd:23
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      sameAs:https://doi.org/10.1038/s41467-025-59874-0
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         Cancer therapy
         Drug discovery
         Machine learning
         Science
         Humanities and Social Sciences
         multidisciplinary
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