2. Academic Validation
  3. 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

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

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.

Figures
Products