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
Wei-Chieh Yu, T.Y. Yeh, Chih-Hung Ye, Patrick Chun Theng Chong, Yi-Hsun Ho, Dorothy Kazuno So, Kah Yi Yap, Guan-Ru Peng, Chi-Hsuan Shao, Ajit Dhananjay Jagtap, Ji‐Wang Chern, Chen‐Si Lin, Shau‐Ping Lin, Shuei‐Liong Lin, Shu‐Han Yu, Chao‐Wu Yu
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.