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

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

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. alex@insilico.com.
  • 8 Insilico Medicine Shanghai, Ltd., Shanghai, China. alex@insilico.com.
  • 9 Insilico Medicine Hong Kong, Ltd., Hong Kong, China. alex@insilico.com.
  • 10 Insilico Medicine US, Inc., New York, NY, USA. alex@insilico.com.
PMID: 39663371 DOI: 10.1038/s41587-024-02503-w
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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