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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.
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      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine US Inc,1000 Massachusetts Avenue, Suite 126, Cambridge, USA
      name:Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Phase 2, Hong Kong Science Park, Hong Kong, China
      name:Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, Shanghai, China
      name:Insilico Medicine US Inc,1000 Massachusetts Avenue, Suite 126, Cambridge, USA
      name:Insilico Medicine AI, 6F International Renewable Agency (IRENA) Building, Masdar City, United Arab Emirates
      name:Insilico Medicine US Inc,1000 Massachusetts Avenue, Suite 126, Cambridge, USA
      name:Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Phase 2, Hong Kong Science Park, Hong Kong, China
      name:Insilico Medicine AI, 6F International Renewable Agency (IRENA) Building, Masdar City, United Arab Emirates

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