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

  • Nat Biotechnol. 2024 Dec 11. doi: 10.1038/s41587-024-02503-w.
Yanyun Fu  1  2  3  4 Xiao Ding  1  2  4 Man Zhang  1  2  3 Chunlei Feng  1  2 Ziqi Yan  1  2 Feng Wang  1  2 Jianyu Xu  1  2 Xiaoxia Lin  1  2 Xiaoyu Ding  1  2 Ling Wang  1  2 Yaya Fan  1  2 Taotao Li  1  2 Yushu Yin  1  2 Xing Liang  1  2 Chenxi Xu  1  2 Shan Chen  1  2 Fadi E Pulous  1  5 David Gennert  1  5 Frank W Pun  1  3 Petrina Kamya  1  6 Feng Ren  1  2  3  4 Alex Aliper  1  4 Alex Zhavoronkov  7  8  9  10
Affiliations
  • 1. Insilico Medicine US, Inc., Boston, MA, USA.
  • 2. Insilico Medicine Shanghai, Ltd., Shanghai, China.
  • 3. Insilico Medicine Hong Kong, Ltd., Hong Kong, China.
  • 4. Insilico Medicine AI, Ltd., Abu Dhabi, UAE.
  • 5. Insilico Medicine US, Inc., New York, NY, USA.
  • 6. Insilico Medicine Canada, Inc., Montréal, Québec, Canada.
  • 7. Insilico Medicine US, Inc., Boston, MA, USA. [email protected].
  • 8. Insilico Medicine Shanghai, Ltd., Shanghai, China. [email protected].
  • 9. Insilico Medicine Hong Kong, Ltd., Hong Kong, China. [email protected].
  • 10. Insilico Medicine US, Inc., New York, NY, USA. [email protected].
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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