Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor
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.
Authors
- Yushu Yin
- Taotao Li (ORCID: https://orcid.org/0000-0002-7273-5685)
- Frank W. Pun (ORCID: https://orcid.org/0000-0001-8801-6645)
- Chenxi Xu (ORCID: https://orcid.org/0000-0001-7747-0033)
- Yaya Fan
- David Gennert (ORCID: https://orcid.org/0000-0002-8668-3601)
- Alex Zhavoronkov (ORCID: https://orcid.org/0000-0001-7067-8966)
- Chunlei Feng (ORCID: https://orcid.org/0000-0002-2853-4771)
- Petrina Kamya
- Alexander Aliper (ORCID: https://orcid.org/0000-0002-4363-0710)
- Liang Xing
- Fadi E. Pulous
- Man Zhang (ORCID: https://orcid.org/0000-0001-9600-904X)
- Shan Chen (ORCID: https://orcid.org/0000-0002-6177-5980)
- Ling Wang (ORCID: https://orcid.org/0000-0002-0432-6986)
- Rui Wang (ORCID: https://orcid.org/0000-0003-1723-4746)
- Ziqi Yan (ORCID: https://orcid.org/0009-0003-4045-9721)
- Xiaoyu Ding (ORCID: https://orcid.org/0000-0003-2857-8114)
- Yanyun Fu
- Feng Ren (ORCID: https://orcid.org/0000-0001-9157-9182)
- Jianyu Xu (ORCID: https://orcid.org/0000-0002-0870-7671)
- Xiaoxia Lin (ORCID: https://orcid.org/0009-0003-7698-8748)
- Xiao Ding (ORCID: https://orcid.org/0000-0002-5838-0320)
Institutions
- Insilicos (United States) (US)
- Insilico Medicine (United States)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2024-12-11
- DOI
- https://doi.org/10.1038/s41587-024-02503-w
- Citations
- 36
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 8.42