Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor.

Fu, Yanyun; Ding, Xiao; Zhang, Man; Feng, Chunlei; Yan, Ziqi; Wang, Feng; Xu, Jianyu; Lin, Xiaoxia et al. · Nat Biotechnol · 2025

basic_science · Level V

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Abstract

Hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors have been approved for treating renal anemia yet have failed clinical testing for inflammatory bowel disease because of a lack of efficacy. Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models.

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