Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor
Hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitors have been approved for treating renal anemia, yet have failed clinical testing for inflammatory bowel disease (IBD) due to lack of efficacy. We use a multimodel multimodal generative AI platform to design an orally gut-restricted selective PHD1/2 inhibitor, which exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models. Overall design: Around 100 mg of colon tissues were collected from sham or TNBS-induced colitis mouse models treated with either vehicle or ISM012-042 on day 2 post-colitis induction.