Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors
Abstract 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...
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| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59874-0 |
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| author | Congying Pu Hui Cui Huaxing Yu Xin Cheng Man Zhang Luoheng Qin Zhilin Ning Wen Zhang Shan Chen Yuhang Qian Feng Wang Ling Wang Xiaoxia Lin David Gennert Frank W. Pun Feng Ren Alex Zhavoronkov |
| author_facet | Congying Pu Hui Cui Huaxing Yu Xin Cheng Man Zhang Luoheng Qin Zhilin Ning Wen Zhang Shan Chen Yuhang Qian Feng Wang Ling Wang Xiaoxia Lin David Gennert Frank W. Pun Feng Ren Alex Zhavoronkov |
| author_sort | Congying Pu |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-cfc8ea08294e4c67958edb1f994601df |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cfc8ea08294e4c67958edb1f994601df2025-08-20T03:48:19ZengNature PortfolioNature Communications2041-17232025-05-0116112310.1038/s41467-025-59874-0Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumorsCongying Pu0Hui Cui1Huaxing Yu2Xin Cheng3Man Zhang4Luoheng Qin5Zhilin Ning6Wen Zhang7Shan Chen8Yuhang Qian9Feng Wang10Ling Wang11Xiaoxia Lin12David Gennert13Frank W. Pun14Feng Ren15Alex Zhavoronkov16Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine US Inc,1000 Massachusetts Avenue, Suite 126Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Phase 2, Hong Kong Science ParkInsilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaInsilico Medicine US Inc,1000 Massachusetts Avenue, Suite 126Abstract 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.https://doi.org/10.1038/s41467-025-59874-0 |
| spellingShingle | Congying Pu Hui Cui Huaxing Yu Xin Cheng Man Zhang Luoheng Qin Zhilin Ning Wen Zhang Shan Chen Yuhang Qian Feng Wang Ling Wang Xiaoxia Lin David Gennert Frank W. Pun Feng Ren Alex Zhavoronkov Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors Nature Communications |
| title | Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors |
| title_full | Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors |
| title_fullStr | Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors |
| title_full_unstemmed | Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors |
| title_short | Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors |
| title_sort | oral enpp1 inhibitor designed using generative ai as next generation sting modulator for solid tumors |
| url | https://doi.org/10.1038/s41467-025-59874-0 |
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