Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-β-Induced Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2023 Aug 10;66(15):10528-10557. doi: 10.1021/acs.jmedchem.3c00644.
Wei-Chieh Yu  1 ,  Tsung-Yu Yeh  2 ,  Chih-Hung Ye  1 ,  Patrick Chun Theng Chong  1 ,  Yi-Hsun Ho  2 ,  Dorothy Kazuno So  3 ,  Kah Yi Yap  1 ,  Guan-Ru Peng  1 ,  Chi-Hsuan Shao  2 ,  Ajit Dhananjay Jagtap  2 ,  Ji-Wang Chern  2 ,  Chen-Si Lin  4 ,  Shau-Ping Lin  5  6  7 ,  Shuei-Liong Lin  8  9  10 ,  Shu-Han Yu  1 ,  Chao-Wu Yu  2
Affiliations
  • 1. Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
  • 2. National Taiwan University, School of Pharmacy, College of Medicine, Taipei 100, Taiwan.
  • 3. Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei 106, Taiwan.
  • 4. Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 106, Taiwan.
  • 5. Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 6. Center of Systems Biology, National Taiwan University, Taipei 106, Taiwan.
  • 7. The Research Center of Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 106, Taiwan.
  • 8. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 9. Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
  • 10. Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei 100, Taiwan.
PMID: 37463500 DOI: 10.1021/acs.jmedchem.3c00644
Abstract

Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.

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