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

Idiopathic pulmonary fibrosis is incurable, and its progressionis difficult to control and thus can lead to pulmonary deterioration.Pan-histone deacetylase inhibitors such as SAHA have shown potentialfor 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 platformto rapidly screen for HDAC inhibitors that effectively mitigate TGF-& beta;-inducedpulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblastprescreen and yielded five hits. In the second stage, human pulmonaryfibroblasts (HPFs) were used, and four out of the five hits were testedfor caco-2 permeability and liver microsome stability to give twopotential leads: J27644 (15) and 20. Thisnovel two-stage screen platform will accelerate the discovery andreduce the cost of developing HDAC inhibitors to mitigate TGF-& beta;-inducedpulmonary fibrosis.

Automated summary

Idiopathic pulmonary fibrosis is a difficult-to-control, incurable disease that can lead to pulmonary deterioration. The use of pan-histone deacetylase inhibitors has shown potential for reducing pulmonary fibrosis, but with off-target effects. This study aims to discover selective HDAC inhibitors for mitigating TGF-β-induced pulmonary fibrosis through a two-stage screening platform. The platform successfully identified two potential leads, J27644 (15) and 20, which can accelerate the development of HDAC inhibitors and reduce the cost.