Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors

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 and Alex Zhavoronkov ()
Additional contact information
Congying Pu: Pudong New Area
Hui Cui: Pudong New Area
Huaxing Yu: Pudong New Area
Xin Cheng: Pudong New Area
Man Zhang: Pudong New Area
Luoheng Qin: Pudong New Area
Zhilin Ning: Pudong New Area
Wen Zhang: Pudong New Area
Shan Chen: Pudong New Area
Yuhang Qian: Pudong New Area
Feng Wang: Pudong New Area
Ling Wang: Pudong New Area
Xiaoxia Lin: Pudong New Area
David Gennert: Suite 126
Frank W. Pun: Hong Kong Science Park
Feng Ren: Pudong New Area
Alex Zhavoronkov: Suite 126

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59874-0

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