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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